I'd like to thank the organizing committee for inviting me. That's me. Um And I'm just gonna give a sort of a little bit of a, I guess that this one would be historical background on immunotherapy in the front line treatment. I'm gonna concentrate on front line treatment of lung cancer. Uh These are my conflicts. Um So I think what we've learned with um the uh introduction of immunotherapy checkpoint inhibitors, I should say. So, the treatment of patients with non small cell lung cancer is that uh you know, biomarkers can be very, very helpful in this disease. We've used uh PDL one as uh our favorite biomarker and we've gone back and forth since 2, 2012 or 13 when this biomarker was sort of uh introduced as to whether this is a good biomarker or not. So, it is an IHC based assay. It comes with all the caviar that an IHC based assay comes with uh the heterogeneity tumor. Uh the, the where the needle goes might matter. But if you look at the collection of data that's available out there, PDL One has been a very good predictor of response to checkpoint inhibitors to the extent that if you have somebody PDL 180 90% you are very comfortable to say that single agent checkpoint inhibitor can be extremely helpful in this disease. So despite all of its deficiencies, this has been a pretty useful uh biomarker. So in a very simplified world, we can divide patients and having high PDL one or low PDR one. Um and some of the options that you see um are applicable to both groups of patients. One group might benefit more from a specific treatment versus the other. And this is an area where there is a lot of controversy because we don't have head to head comparisons for a lot of these um uh regimens that we have available. I would also introduce this new wrinkle into this, that that's using the genomic data that now we have, we have a robust data set. Now of all the patients with non small cell lung cancer who are getting genomic analysis and we have learned that some of these such as SCK 11 keep one, which is the subject of the next talk. In fact, have implications. We also know we heard from doctor B there that if a patient has one of the molecularly driven tumors. Egfr A any of those, there is no data at this point to suggest that use of a checkpoint inhibitor is going to be helpful. So we do have additional biomarkers that I think we need to introduce and bring into the clinic. Historically, we started looking at single agent drugs uh in patients with uh uh non mule lung cancer treatment naive. On the left hand side is the keynote 024, Pembroke PDM 1/50 percent. Um And on the right hand side is Checkmate 026, which we were heavily involved with. And in fact, on the steering committee and all that for that study using Neom A versus chemotherapy PD A 1/1 percent with the final analysis and subjects of P A 10 5%. And the results was pretty clear PD A 1 50% or higher pembrolizumab was superior in overall survival to chemotherapy. And overnight this became the standard of care for patients with high PDL one. Unfortunately, for the 026 study, the PDL one marker of being one or at the final analysis, 5% did not show superiority of Nevo over chemo. Uh I would also like to point out that it doesn't show inferiority necessarily, but the study was designed to be a superiority study and therefore did not meet the primary end point. We've come a long way. We now have five year survival data for keynote 024, actually, maybe beyond that. But we've all selected five year as a benchmark for saying whether someone is cured for a metastatic disease or not. And I want everybody to take a moment again to really look at this and think about how far we've come with lung cancer. It is about 20 25% of our patients with metastatic non muscle lung cancer. Some of these, these patients had brain metastases at the time of entry and 25 30% of these patients are alive. Five years down the road. That is a huge accomplishment, something to celebrate and something to be very thankful to. Maybe we got lucky, maybe drugs like PM bro and Evola and other c inhaler don't come along more than once in a lifetime of a medical oncologist, but I am super happy that I was here and I was able to watch this develop because we never had anything like this in the past. I think that is huge for us to consider and the take home message. Despite all the negativity that is around metastatic lung cancer, we have made progress and hopefully the progress will continue. Well designed study Judy Bremer, who Julie Bremer who was just here was uh a major uh uh contributor to this trial. You notice that the patients on the platinum doublet chemo actually had the option of giving getting pembroke at the time of progression crossover. Despite all of that patients who started with Pemra on the study that far better and then the treatment was continued for two years. And on the table, on the below, you see, certain percentage of these patients actually had recurrences when back on Pembrey, the longevity of some of these responses that you can see and the enormous power of activating the immune system if greater than 50% can benefit from single agent. Pem, bro, can anybody with great than 1%. So the experiment that NAAB did with Checkmate 026 was repeated with pembrolizumab and keynote 042, a more global study, slightly different patient pop that would be getting in the US. But by and large as lung cancer people here, we sort of have decided that this study was not positive and that the majority of the of the benefit came from patients with PDL 1/50 percent and not so much from patients with lower levels of PDL one expression. In fact, the European societies decided not to approve single agent Pemra for use in this setting. However, the US FDA curiously enough approved this. But if you go to the US FDA today and you say that you want to do a randomized face three study in Pedia 1 1% or higher with Pembroke as your control arm, they'll kick you out of the FDA. We have other checkpoint inhibitors who've shown similar uh clinical activity. A tazo eab A PDL one went through a very similar program uh program development. And if you look at uh the, the curve more on the right hand side, if the PDL one expression, which here was defined a little bit differently with IC three meaning immune cell three. the overall survival was this uh was still good. So again, no matter how you cut the PDL one, if it is described as being high level of expression, the clinical outcome is good for those patients. The comparator is the PD 1 50% or higher from Keynote 024 Selim. Another checkpoint inhibitor. Again, a very similar study, you kind of wonder if there is innovation anymore in clinical trials because everybody does the same study. But the studies are highly effective. Again, high PDL one expression is associated with better clinical efficacy for both P EFS and overall survival. What I like about this study is that they actually looked at higher cut points for PDL 1 60% 80% 90% the higher the level of PDL one, the better the clinical efficacy. In fact, we are not debating within thoracic community and we do trials that maybe 15% is too low. Maybe we need to go a little bit higher. It would be a lower patient percentage who would benefit from this. However, the clinical efficacy could be hugely magnified and that can have implica implications for future clinical trials by chance. If you just get 8% more patients with PD 1/90 percent in your study, the results could be completely skewed. So something to pay attention to for future studies. Well, if a single agent immunotherapy is good, what about our favorite combo? Let's just add chemo to it. It's like I love a hamburger, but it's better with fries. So let's add chemotherapy to it. That's the French fries of lung cancer community, right? So we come to keynote 189 a very simple phase three study. I like the way these studies are done. Why you ask one simple question and you get a clear answer. It's either a yes or a no. And usually there's not a lot of debate. So these are the way we wanna try to design our trials. So what's the premise here? Chemotherapy is the standard of care, non squamous histology. Regardless of video. The one, what if we just took two groups, one group just got chemo, the other group, chemo pembrolizumab. And we're still gonna allow a crossover such that if the patients on the chemo arm are progressing, they can get something that we think is effective. And that's the checkpoint inhibitor, every single clinical parameter that we monitor PFS response rate, overall survival in a intent to treat patient population. Everybody who got a dose of any other drugs was in favor of the combination with chemo and pembrolizumab. This was presented at A AC R on a Sunday by Monday morning. No one in the US was getting chemo alone even though it took a while to get it approved, you can look at PDL one expression and regardless of the level of PDL one. So PDL one high is benefiting from this PDL. One low is benefiting from this and intermediate. The question becomes well, why PDL one negative again, goes back to the heterogeneity of PDL one testing with the immuno chemistry and probably the inadequacy of that. However, there are probably other explanations for it. So what also happened in the study was that we figured that if we add chemo to a checkpoint inhibitor, we're actually not increasing the immune related adverse events. So we're not seeing more pneumonitis, we're not seeing more colitis so we can have our cake and eat it too. So our patients are benefiting from something that's highly effective, but it doesn't add to the toxicity of the regimen. We have five year survival data with this study also. And again, regardless of the level of VDL one expression, and I fully realize that we still have a lot of work to do. Those curves are not staying flat, they are coming down. Unfortunately, so many of our patients are succumbing to this disease. However, compared to what we were doing just 10 years ago, again, major improvement with five or six year survival advantage. Why is that important? Well, we've seen in the world of lung cancer, if you've been doing this for 2030 years, studies that are positive at two years and negative at five years, this happened, it used to happen in lung cancer, but we don't see it quite as much. So, when I see a study that can actually have five year survival data that says what we saw in the year and a half to two years still persists at five years. I tend to believe the data a little bit more better and makes me more comfortable to talk to my patients about accepting something like this. Here's another trial in power 150 genetic used a slightly different chemo background carboplatin ale Taxol be theism after this study. This is the old E COG standard for treatment of metastatic lung cancer. Why? Because E cog 4599 said Carbotaxol BEV gave you a median OS of 12 months versus 10 months with carbotaxol. And we were celebrating at as o when we got 12 months out of bevacizumab. Nonetheless, this study was done with the addition of a TAO to that background versus a Taso chemo alone. So a three arm study, they did allow patients with EGFR and out post TK I to enter the study, which is a, a little bit of a deviation from some of the normal studies we have done in the world of lung cancer. I've highlighted that because the speakers highlighted about 100 patients with EGFR A who got the quadruple therapy of Carboplatin Paclitaxel bic is app and a Taoism app. And they seem to have a higher clinical efficacy in that study. When the, the data was looked at by the US FDA and others, they decided not to approve the regimen in that particular group of patients because there was a lot of heterogeneity in the EGFR mutation. And there was not certainty that this is going to be a good treatment option for that patient population. Although in a complete departure from what's normal in Europe, they approved this. So I can't figure out the Europeans ever. So if you look at the intent to treat patient population without molecular alterations, the quadruple regimen is better than standard chemotherapy. But something interesting happens when you look at and isolate the EGFR positive patients in the study. The blue line, left upper hand corner clearly indicates that if you have the quadruple versus the triple regimen, there might be an interaction between the Taso IAB and Bevis app improving the improving the clinical efficacy in this patient population. This is probably one of the first signals we had that maybe there is a way to introduce immunotherapy to the treatment of patients with molecular driven tumors. This area is still evolving as you heard from doctor, both, both doctor both and doctor treat have been leading a national study randomized to try to address this question, post post TK I in patients with EGFR positive disease controversial area because there's studies for and against that from global trials that have been done. So we need to stay tuned until we get more studies. Yet another trial in power along this is also climb with chemotherapy again, very similar results as you would anticipate addition of chemotherapy and IO can be better in terms of overall survival, progression free survival. And that it doesn't really add significantly to the toxicities of either regimen. Bunch of us who are sort of on the younger side when we were doing these studies decided that what if we can get rid of that French fries and replace it with like a milkshake? What if we don't do chemo? Maybe we can do ioio and spare people some of the toxicities of chemotherapy. So we came up with this brilliant idea of using Piab AC TL A four antibody with evola, an anti PD one drug that we had just talked about. And what if we offered that to two groups of patients, those with PDL one positive disease and those with PDL one negative tumors with the idea that a dual immunotherapy could be better than chemo and maybe even better than chemo plus noom. Again, we were on the steering committee for this. We put a lot of patients on this and actually it took us several years to get to this phase three because we did the phase one, we did the phase two to find the right dose and schedule a delivery of both of these drugs. So an enormous number of patients went on this first one, phase one, phase two trials um to to for us to be able to do this phase three study six year survival data from checkmate 2 to 7. I would fully admit that this is one of those trials that again has become a little bit of a controversy in our world. Why? Because it was too complicated, too many different groups, too many questions being asked. And I think that was something that we should have avoided when we were designing these large clinical trial to address an unmet need. However, the results are still standing. It is kinda like, you know, you like Coke or Pepsi right now. If you're a Coke person, you always like Coca Cola, that's chemo I or if you're like a Pepsi guy, you always like Pepsi and that's 227. I would say that and I am completely biased because of my involvement with the study in my clinic. PDL one negative tumors. Again, this is my view and my bias. I preferentially use an epinal combination perhaps with chemo the P Allah the nine L A regimen. I'm gonna show you, but that's not the norm in majority of thoracic uh thoracic clinics. Yet we have six year survival data. As you can see on these graphs, there is a tail to this curve, look at the tail of the curve for the A P Nevo in both PD 1/1 percent or less than 1%. Again, this becomes another important thing for us to follow. The problem is we're not good at figuring out who's at the tail of that curve, who is really benefiting and who's dropping off by three months. And I think that's where the field has sort of fallen apart because we haven't developed other biomarkers. We know that depth of response is also important. So if you have an 80% response, you do better with this regimen. We also know that regardless of ed a one expression that uh that stands. So the, the depth of response and the durability of response can give you a little of a clue as to how the patient is going to do with this particular regimen. If epinal is good, what if we do chemo added to it? It took it, it was a battle to convince everybody to do only two cycles of chemo. Why do you wanna do chemo? The old idea was that if you do chemotherapy, you actually induce this immunogenic cell death, which I think it's been proven to be wrong. You're not doing that with chemo. So if that was the argument back then maybe two cycles is enough, you don't have to subject patients to four cycles and then maintenance and everything else. We convince everybody to go along with that regimen. The other problem is that by the time the study was activated, the practice in the US had become chemo IO. So the control arm of chemo alone was not adequate for us in the US. So the study was done mostly in Europe and some of the other countries. But the outcomes again are shown. This is at the time of initial presentation. PDL one less than 1% two cycles of chemo epinal superior to chemotherapy in PFS overall survival and duration of response. It is superior in PD 1/1 percent. It's even good in PD, 1/50 percent. So now you can do IO alone if you have high PD one, you can do IO plus chemo, you can do a PE O and you can do nine L A. So depending on which side of bed you come, you get up on, you can decide what you want to do. They're all joking aside, everybody comes into these treatments with their own biases and again, patient selection and having that discussion with the patient. What are the toxicities? What are the duration of therapy? What can be anticipated becomes really important? The problem still is that I cannot look a patient in the eye and say, I think you'll benefit from the nine L A regimen as you see here or you can just get away with single agent checkpoint inhibitor and you don't need anything else that ability still does not exist. We have five year survival data from nine L A as shown here that busy graph in the Meadow. Those are patients who've had long lasting clinical benefit on either arm of the study. When you look at the standard clinical criteria and PDL one expression. It is still hard to tell you who's really gonna benefit from this and who's not an interesting tidbit though is the graph on the right hand side, those are the overall survival on patients who had discontinued ep because of the toxicity. And the graph on top is the ones who stopped the treatment that was interesting. So the emergence of immune uh related adverse event could actually indicate a better clinical efficacy. Another immunotherapy duo Dorve Trey has also gone through a very similar clinical development. This large poi uh uh Poseidon trial was done three arm study. Um looking at Dova chemo, Dova Trey plus chemo or just chemotherapy. Again, if you look at the data, OS and PFS compared to chemo is better with the quadruple therapy. As you see on these curves, look at the PDL one negative group. The addition of creamy maab in this particular group of patients actually did improve the overall survival of the patients with PDL one negative tumors. Again, the idea that perhaps PDL one negative tumors could benefit from AC TL A four inhibition is something that many of us are sort of thinking about and trying to design studies uh around that. What happens if you sort of decide to give chemotherapy with immunotherapy with somebody with a high PDL one expression or if you decide to do dual immunotherapy, we don't have clinical trial level data yet. But what we have is real world data sort of suggesting that for patients with high PDL one expression, the addition of chemotherapy to checkpoint inhibitors do not necessarily improve overall survival. This is from real world data. So you have to take it with a grain of salt. But it is an idea that I think is testable. I'm gonna show you a study, we tested it and here's the, the trial. This is the study that Doctor Chang and I ran. Uh I, I was a peacock uh P I. Doctor Chang, the swag P I. And we basically ask those questions as part of this practice in forming study. Does it matter if at the time of progression on a checkpoint inhibitor, you add chemotherapy to it. Now, we used PDL one of 1% or higher for this as a study, entry criteria. Not 50%. The study completed accrual about a year ago and we're waiting for the results. So perhaps we'll have some stuff coming up. What else are we doing nowadays? Well, we've introduced antibody drug conjugates and by specific antibodies to the front line antibody drug conjugates have been very popular. We did not discuss them today because of time constraints. But the idea of using an antibody drug conjugate in the front line is rather attractive because it might allow you to eliminate one of the cytotoxic chemo drugs that you're using because in a way an A DC is sort of a targeted chemotherapy delivery. This study has been ongoing. Again, we're participating in a, in a version of this trial where uh in this case, a trope two A DC is being used in combination with Pembrey with um A carboplatin and checkpoint inhibitor to see if we can replace. One of the chemotherapy drugs toxicity has been an issue. As you can see on the graphs there, stomatitis, nausea, decreased appetite, all of these have seen with the A DC. But at the same time, you are getting pretty robust clinical activity and whether you're using a doublet or the triplet here. So if I can really get a 6050 to 60% response rate and I have deep durable responses and I can replace a chemo maybe it would be worth. But we have to come up with a way to mitigate some of the toxicities. From my point of view. The biggest problem with the study is that we're trying to replace a very well tolerated chemo in Pitre said with something that has additional toxicity. And again, that has to be a balance and a discussion with the patients briefly by specific antibodies have gained a lot of attention. Why um giving two antibodies together has always been a good idea. But what we're finding out uh is that when you do two different antibodies at the same time to access, these are a little bit more and the clinical efficacy isn't quite there. The concept of the bici antibody one antibody that targets two separate things, two separate tumor antigens. Or in this case, VEG E and PD one is attractive because the binding to one antigen changes the dynamic of the binding to the other antigen. And in fact increases the clinical efficacy while not increasing the toxicity seen with these bio specifics. This drug has been tested in China. It has made its way to the US. We have us studies going and this was a simple study of going head to head versus pli zum in anybody with PD 1/1 percent. As you can see PFS in this study was in favor of the biosci antibody uh in this harmony. Two trial and the drug is Ivano. So you are going to hear a lot more about this drug and a number of different clinical trials. Are there other innovations that can be brought into this space? Well, potential innovations such as tumor treating fields have to be discussed. This was presented at Asco about a year ago. Tumor treating fields uses the concept of intercurrent uh electrical currents going through a patient. This has been tested in mesothelioma and used there. It's been tested in patients with uh primary main tumor. It's been approved there and it's in use. The study was presented by Doctor Tia Tiana Leo from um Emory University. This is an older design. The study was designed when checkpoint inhibitors are still being used in the second line setting and the the design was simply standard of care treatment versus the same standard of care plus tumor treating fields. And the graphs that's shown there sort of suggest that there might be an advantage to using tumor treating fields in this patient population. So the question really is, can this be introduced to the front line space because that's where we concentrate the majority of our treatments? And is there a way to integrate this into our everyday care of our patients? There are studies that are testing that hypothesis. So hopefully we learn more about them and these are some of the toxicities reported in this, you know, dermatitis, as you would expect is the most common adverse event seen. But some of the other adverse events were not really uh exaggerated by using a tumor treating fields. So, although we've come a long way, we've sort of hit a little bit of a plateau in the treatment of front line patients with metastatic non muscle lung cancer. I think antibody drug conjugates and particularly by specific antibodies are uh providing some promise that we can overcome that that plateau, at least to some extent, molecular signature has become really important. And as always patient preferences, toxicity profile and quality of life should be considered when we're selecting these treatments. Thank you for your attention.
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