Suresh S. Ramalingam, MD explains Non-small Cell Lung Cancer (NSCLC), and identifies therapy for patients with driver mutations such as EGFR, ALK, and RET. Dr. Ramalingam also presents immunotherapy options for patients without driver mutations, and discusses new emerging therapies.
Back to Symposium Page » It's now my pleasure to introduce our next speaker, Dr Suresh, from a Lingam professor of hematology and medical oncology at Emory University School of Medicine. Dr. Ramalingam will be speaking to us on updates and non small cell lung cancer with emphasis on front line therapy. Dr. Ramalingam is well known for his work in the field of small cell and non small cell lung cancers, and we're very pleased to have him with us during this conference. If you have questions you'd like to ask, please use the ask a question chat function and will be collating questions for the panel discussion. Please, everyone welcome Dr Ramalingam. I would like to start by thanking the organizers for inviting me to present on an exciting topic, which is lung cancer. There have been a lot of exciting advances in the field of lung cancer in the past few years, and 2020 was no exception. A number of new agents have been approved. A number of new strategies have entered our clinic and we're beginning to make a difference for our patients by providing not only improved survival but also improved quality of life. My presentation today will focus primarily on non small cell lung cancer and specifically in first line therapy treatment of non small cell lung cancer. These are my disclosures. So what I'm going to cover today is shown in the slide. I'm going to talk about patients with driver mutations. In the first part of my talk, we'll talk about advances in E Jafar mutated lung cancer. We'll talk about out positive lung cancer and read positive lung cancer. These are areas where there have been new approvals, new indications by the FDA this year. For the interest of time, I won't be able to cover all the various targets, but we'll hit the key highlights. And then we'll talk about the management of patients who don't have driver mutations. This is an area where we're using immunotherapy for our patients, and I'll talk about various immunotherapy options available. And finally, I'll finish up talking about some emerging novel options that you might want to keep your eyes out for in 2021 as potential new drugs to be added to our therapeutic armamentarium against cancer. Now, if you look at the FDA approvals in the year 2020 for lung cancer, it has been a very exciting time. You can see the number of new indications that have been approved, and this slide summarizes them all. This is just for the year 2020 if you look at non small cell lung cancer. We had an approval for medics on 14 mutation just yesterday. As a record, this presentation to Partner Cap Magnet was approved in 2020 Red Fusion. There are two drugs approved out. We have a number of immunotherapy options approved for non small cell lung cancer this year. Al E. Jafar and we also have an approval for targeted therapy and early stage disease. And we'll talk about the data supporting that. We also have seen approvals in small cell lung cancer and mesothelioma. This year, there were two strategies approved in small cell lung cancer. One involves using chemo plus interval. A map lawyer Ben Acted in, which is now approved for salvage therapy, is based on Phase two study, and it is an accelerated approval. And finally, Nevo and BP is a combination that has received approval for first time therapy of pleural mesothelioma. I'm not going to cover the small cell and mesothelioma topics in the interest of time. But I'm going to go over all the other approvals that you see on the front half of the top half of the slide so we can, uh, see how best they fit in in our clinical practice. So let's start with targeted therapy. We know that nearly 50 to 60% of stage for non small cell lung cancer patients have non squamous histology, particularly adenocarcinoma. Now, in 2021 our recommendation is that every patient with adenocarcinoma of the lung should have broad molecular profiling. NGS Why NGS? Because there are seven targets that are that have approved therapies. So it's easy to get NGS testing done. So we have the necessity genomic information of that particular patient so we can make appropriate treatment decisions. I would also make the point that, to the extent possible, wait until the molecular profiling results are back before we start therapy. It is not a good idea to start something empirically and then switch to something else in the early days of treatment, particularly when you think about T K I and immunotherapy mixing with each other, there are potential toxicity consequences. If there was a patient situation where one does not have the luxury of time to wait until the molecular testing is back. Then my suggestion would be to just start them on chemo Doublet, our chemo plus system as appropriate. Don't start immunotherapy in the front line. Wait until the molecular testing results are available. If the patient has a target, then you can easily switch away from chemo to a targeted therapy. If there is no treatable target, then you can add immunotherapy on top of chemo at that time point, as opposed to starting with chemo immunotherapy. That would avoid a lot of potential toxicities when you make the switch to target at 30 let's first talk about E. Jafar mutated lung cancer. We know that idea. Far mutations are seen in about 15% of long and no customer patients in the Western world. Exxon, 19 and Exxon 21 are two common mutations. These are the ones that are readily responsive to Titus and Chinese innovation. This is the Flora study. You're familiar with this? We published these results in the New England Journal about a year ago. This trial was designed to evaluate the role of customer up in the front line setting well. Why Awesome art Lab number one. It's a third generation drug which has greater selectivity to the mutated receptor as opposed to the wild type, so it has better toxicity compared to the first or second number two. It is also protective against T 790 and mutation, which is the most common resistance pathway if patients are treated with first or second generation drugs, and third, it has good CNS penetration and therefore has activity against brain metastases. So in this study, we compared Awesome Martin of 80 mg per day head to head with a lot about Jeff Fitness. The primary endpoint was PFS. There was a substantial improvement and median progression free survival. I'm not showing you that data because you're very familiar. The median PFS with Ozzy Martin was about 19 months in the control group. It was 10.2 months. Hazard ratio was 0.46 favoring his apartment, and that resulted in the FDA approval of us a magnet for first line therapy. On this slide, you see the overall survival results. There was a substantial improvement in overall survival from 31.8 months in the control group to 38.6 months. Almost seven months improvement at the median for patients treated with US A murder with the hazard ratio of approximately 70.8, which was statistically significant. Keep in mind that in this trial we allowed crossover for patients in the control are. In fact, nearly 31% of the patients in the control group went on to receive subsequent awesome art therapy if they were eligible for crossover therapy. And despite that crossover, we see the survival difference. And this argues against the hypothesis that you can sequence first generation drugs first, are second generation drugs first and then wait until T 7 90 happens and then give them a smart. That's exactly what was done in Flora study, and we still saw a survival benefit with front line Also Martin. So these results justify the NCC and designation of us emerged as the preferred first line therapy drug for E g F R. Mutated lung cancer. Well, what's the next? We're beginning to understand the resistance mechanisms that happened after exposure to assume Martin. This is a slide from a report we presented Ehsmoh meeting a couple of years ago. This is looking at plasma data in patients treated with Martin on the floor. A study first point I want to make is we did not see a single case of p 7 90 a mediated resistance when patients are treated with Osama. The second point is when you look at other common mechanisms. There was no suggestion that somehow the treat the US behaved in a more aggressive manner when patients developed resistance to awesome compared to the other e g a 40 ks. In fact, some of the common mechanisms we see are very similar. With the exception of P 790 with the 1st and 2nd generation drugs, we see the C 797 s mutation in about 7 to 10% of the patients met pathway alterations in is about 15% of the patients. What does this mean? Well, there are now ongoing trials that are looking at combination approaches targeting the specific resistance pathway in order to overcome assistance in these patients. So these trials are ongoing, and we hope to see data from this one particular combination for which we have data are combination of met inhibition with Martin in a trial reported in Lancet oncology last year, where Met amplified patients benefited from the combination with robust response there. So, based on all of these, were now entering into a time where understanding candidate resistance mechanisms could help us guide appropriate therapies. At this point, however, when patients progress on a similar chemotherapy remains the go to approach. Now keep in mind that a small percentage of the patients can convert to small cell histology and the progress on a T. K. So if you see an aggressive progression pattern, suggest getting a biopsy so you can diagnose the small cell and treat them with a small cell type of fraudulent. What are some of the other indications for E. Jafar innovators? Well, this is a combination that has been approved. Ramos serum Apples are locked up in the front line setting. This is also an E jafar mutated patient population. This study, how were excluded patients with brain metastases and what they went on to show is the combination of lot number and Ramos. A mob when compared to a lot of Babylon, resulted in a significant improvement in progression free survival. The median PFS was stronger and a half months in the control group and 19.5 months in the experimental group with the combination. The survival results of this study are not available at this time. We have seen other studies where E g a. 40 ks were combined with this is a map, and in some of those studies, while PFS was improved, there was no difference in overall survival. So how this regiment fits in into the frontline space at this time is not known. I would point out that there is an ongoing Eckhart trial looking at UC Martin up with or without basis, a map in the front line therapy setting, and I hope you would participate in that trial. Now. Perhaps the most exciting development in the easier Far field is the Adora trial that was reported at ESKO 2020. This was an agile in trial. The goal was to see if moving also merge into the adjuvant therapy setting will result and improve patient outcomes. So they enrolled patients with Stage one B two and three, a non small cell lung cancer. These patients were screened for each of our mutations. They all had surgery and after surgery, they were treated with standard of care adjuvant therapy as appropriate, and after that they were randomized to us. So Martin or placebo and in this case, also Martin was given for three years. The trial also allowed patients who did not get chemotherapy. These are the small us that one might not have felt. The need to give chemo are situations where patients did not want to get chemotherapy. So the question was awesome. Motor versus placebo. What's the impact on disease, free survival and secondary outcome? What is the impact on overall survival? This trial ended up being a new blinded early by the by recommendations from the data monitoring committee because the results were overwhelmingly in favor of the awesome organic growth. This is the primary endpoint, which is disease free survival in patients with Stage two or Stage three a disease. When you look at the hazard ratio, it is 0.17 with high level of significance, and you can see the two year DFS numbers 44% in the control group and 90% for patients treated with awesome so clearly robust difference in disease free survival. We also saw from a subsequent report that the incidence of brain metastases was much lower during the time period of follow up for patients treated with Martin compared to the control group, the three year follow up data are relatively immature. The study results are not mature for overall survival analysis, but we will see that in the next one or two years once those results reach maturity. At this point, the FDA has approved customer for adjuvant therapy of resected non small cell lung cancer patients with energy of our mutation. So this is something that we're beginning to discuss with our patients. The duration of treatment is three years. Some have said well, should we wait for survival results to come back to me, there is a difference in disease free survival between the two arms is very compelling. The hazard ratio is very robust. We have not seen this type of hazard ratio in other cancers. And even while there is a caveat of survival data not being available, I am of the view point that we should offer also murdered patients in the adjuvant therapy setting. This is the forest plot from the study. The question was, Does it matter if the patient's got previous adjuvant chemo? Well, it did not matter. Type of e Jafar mutation didn't make a difference. Asian versus Non Asian did not make a difference. Now I'm not recommending that you skip chemo and go to a salon. I would highly recommend that for patients who have to us greater than four centimeters or have no positive disease, we first give them four cycles of CIS platinum based chemo and then moved to a smart alright, let's switch gears now and talk about alk positive disease. ALC is seen in about 4% of the patients that are now plethora of drugs approved for out positive disease. It's needless to say that Chris Arnold is no longer the go to front line drug for all positive patients electing a brigade nib separate neighbor. All appropriate options lower latinum is likely to enter that space, and I'll show you the results of some of the key studies here. Electing him, which is now approved for front line therapy, has been approved for a couple of more than a couple of years now. Here are the results of the Alex trial, where election it was compared to Chris Arnold and you can see that the improvement and PFS 11 months versus 35 months hazard ratio of 0.47 Elective also has good, tolerable itty profile. So this global Alex trial resulted in the approval of election it when you look at the Alta one long trial, this was comparison of Brigadier, which is another second generation Al Qaeda better compared to Chris Arnold here again, very robust improvement in PFS Almost similar hazard ratio for PFS 0.49 So both of these drugs are approved and both of them have good tolerably profile. But brigade nip. You start at 90 mg per day for the first week. And if the patient does not have any pulmonary toxicity which can happen in a small percentage of patients, you can go to the approved dose of 1 80 mg per day. What about some of the other alk inhibitors? One drug that we saw data from is in Sardinia. This is also a trial that compared in Sardinia, Chris Arnold. We saw a hazard ratio of 0.51 again very similar to what we saw on the previous slide and More recently, the Crown study looked at Laura Latina, which is the third generation, or the next generation alk inhibitor. Larry Lardner was compared to Chris Arnold in this head to head study, and the hazard ratio here was truly remarkable. 0.28 for PFS. The median PFS had not been reached for Latin and was 9.3 months for patients treated with Chris Gardner. When you look at the one year survival rate, you don't see this kind of differences. Sorry, one year PFS rate, 78% versus 39%. So Laura Latin. It is also likely to become available as first line therapy. Drug Lord Latin, as you know, is now approved for patients in the salaries therapy setting. So if you start somebody with Chris Arnold are reluctant to share it. Neighbor brigade number and they progress. You give them your Latin with lower Latin. If there are some CNS side effects that one needs to bear in mind, it can also cause, uh, increase in tribal is rights. So people need to be aware of that those adverse events. But it is a drug that is potentially useful in the front line setting as well. We don't have the survival results from these trials. The PFS results are robust enough for us to make changes to our treatment paradigm. So for me, the frontline drug right now is either electronic or brigadier. When patients progress, I give them Lord Latin neighbors the next line of therapy and then move on to chemotherapy. And when I give chemo, it's usually a Perma trickster based chemotherapy, since it seems to work well in this group of patients. Alright, let's switch gears now. The next targeted agent I want to talk about is capped Magnum. This is approved for Met Exxon. 14 mutation. Medics on 14 mutation is seen in about 3% of non small cell lung cancer. And when you do broad NGS, you will get the results of the medics on 14. Particularly patients with circumvented histology tend to have this particular mutation subject for this group of patients kept Met Inhibitor got FDA approval in 2020. The response rate is 68% for patients who have not received prior therapies, and if you're patient, has already received prior chemo, and such response rate was about 41% There's also a difference in PFS based on whether you give it as first line or second line in the first line setting. It's almost one year median PFS in the second or third line setting. It's about 5.5 months. The dose of the drug is 400 mg twice a day. I would recommend using it as first line therapy if patients have the medics on 14 mutation, I don't have a slide on department, which was just approved less than 24 hours ago. It is also associated with similar response rate and median PFS as what we've seen with kept catnip. So that's also a potential option for patients with maximum 14 mutation. This is the waterfall plot from the Department of Studies, where you see the Response State and the median PFS. This is a group of patients who had received prior therapy as well, so you have to factor that in mind. The dose of the drug is 500 mg every day. Now let me talk about red innovation. Reddit is a target. Red fusions are seen in 1 to 2% of the patients. We now have two good FDA approved options for red and red positive patients sell per catnip is approved. In this setting, it has a response rate of about 85% and previously untreated patients and previously treated patients. The response. It is about 64%. It also has very good CNS penetration, 90% brain response rate for patients and median. PFS is approximately 17 months, so it's super catnip. The dose of the drug is 1 60 mg twice daily. The other retina better approved in the setting is prowl. Setting up. You see the waterfall plot from the Aero Study. These are red positive patients. Some of them are treatment naive. Some of them are previously treated with chemotherapy. The overall response rate is about 60%. Uh, this drug is approved at the dose of 400 mg once a day. So these are two good options for red positive patients. And, uh, it's all the more important that we look for targets Red Met. These are targets that occur in small percentage of patients, but unless we look, we're not going to find it. And it's important that our molecular profiling approach for patients involved testing for these variants All right. So those are some of the key updates in the targeted therapy real. I'm going to switch gears and talk about immunotherapy in non small cell lung cancer. We know that PD l one expression is used for patients with a driver mutation. We should use targeted therapy for patients who don't have a driver mutation. We then look at PD L one expression. If it is greater than 50% we use pretty one innovation alone as monotherapy. That is based on the keynote to four trial here. Pembroke versus Chemo Comparison. The hazard ratio for overall survival is 0.62 You can see that the median survival in this group of patients is over 26 months and remarkably five year survival rate is 32% for PD l one high patients. This for a group of metastatic patients, is impressive and also tells us how far we have come. This is not good news for all patients. We want these results for 100% of our patients, but we're making progress. What about chemo? Plus Pem, bro, This is the keynote +189 trial. This was for non screamers patients we saw the overall survival analysis. We tend to use this for patients who have PD l one expression less than 50%. And in this group of patients, the combination of chemo plus Pembroke is superior to chemo alone. Median survival. 22 months versus 10.5 months with a very impressive hazard ratio of 0.56 We did see the approval of a tease Eliza map in the front line setting. This is a PD l one targeted drug. This is the Empower 1 10 trial, very similar to the keynote 024 trial. A Tiso was compared head to head with chemo in the patient population that had high PD l one expression, uh, greater than 50%. And here we saw a substantial improvement in overall survival. The hazard ratio was 0.59 for patients treated with a visa, and the median survival was 13 versus 20 months. Also favoring it is Elizabeth. So it is a is approved also as monotherapy in the PD l one high patients. So we have to approve drugs, embolism, app, and it is Elizabeth. Now some might think, should we add chemo for patients with high PD l one expression that is not my go to approach. But if I had a patient who is really sick, whose disease is very bulky and very symptomatic And if I felt that I only had one shot to make a difference for that particular patient situation, I would give chemo with member or a diesel for that high pd l one patient with significant symptomatic disease. The patient courses somewhat stable. I would just give immunotherapy a law. We also saw the approval of Nevo and BP in this particular patient population. This is the checkmate 2 to 7 trials. This was a comparison of Nevo plus EP to chemo in both the PD l one high and PD L one negative patients in the PD l one positive patients. There was improvement in overall survival with the hazard ratio of 0.79 Notably, the three year survival rate with BP and Nevo was 33% compared to about 22% with chemo alone. So this tells us the results with BP and Nevo are durable and the median duration of response in this group was approximately 24 months compared to only about five months with chemotherapy. So to me, that is an appealing aspect of the knee. VoIP regiment. That is the durability of the benefit. What about PD L one negative patients here again, the pain evil combination seemed to do very well against chemo. In fact, the hazard ratio of Nevo ap versus chemo with the PD L one negative group was even better with 0.64 and the three year survival rate once again here is 34%. So this regimen is approved for PD l one positive patients N, C. C, and guidelines recommended for both positive and negative patients. And to me, the Low PD L one and the PD l one negative patients are really a group of patients where I think about the check me 2 to 7 regimen. We also saw the results of another trial that looked at the combination of chemo plus European naval. This is checkmate nine l a trial here, patients with newly diagnosed non small cell lung cancer were randomized to chemo alone, which is two cycles of chemo with naval and BP. And then they got Nevo and epi alone. So just two cycles of chemo here, and in this trial there was a substantial improvement in overall survival. The hazard ratio was 0.66 Median survival is 15.5 months for the combination, compared to 10.9 months with chemo. The benefit was seen in both squamous and non squamous. The benefit was seen in both PD L one positive and PD L one negative group of patients. So this sentiment is also now FDA approved and merits consideration in patients with newly diagnosed non small cell lung cancer. In both take Me 2 to 7 and nine l A trial. The toxicity profile of Nivola nippy was very tolerable. Remember that the EP does that were given. Lung cancer is not the same dose were given measles. So sorry not were given melanoma. So this tends to be the 1 mg. Every per kilogram. Every six weeks is a dose that's more tolerated and treatment related. Our taxes related treatment discontinuation is seen in only about 15% of the patients. This slide shows the checkmate. Nine early results based on PD l one expression levels, and as I mentioned, the benefit was comparable regardless of level of PD l one expression. So those are some of the key updates in immunotherapy. The future here is in combining novel immunotherapy strategies, adding on to what we've seen with PT one and PT L one. Block it and there are several ongoing trials and the strength finally let me finish talking about couple of emerging novel options. We know that chaos mutations are seen in about 25% of non small cell lung cancer patients. G 12 C mutation Keras GTSI is a sub mutation type or a mutation type that is seen in about 13% of all applications with lung adenocarcinoma, and we're seeing some very interesting, uh, movement here with targeted agents. This is an aggressive, which is a key areas. Get well see inhibitor. This was given to a patient population with lung cancer and the G 20 mutation we saw response. It's about 43% which is impressive, considering that for a long time we've not had any good option for these patients. Another drug that's also being developed in the space. It's perhaps a little farther ahead than that. Aggressive is so aggressive, orally administered to raising cane's here we see results. Response rates with this drug seemed to be about 37% median. PFS is about seven months, and the median duration of response is almost 11 months. So so there is a is an effective agent in the space. It's now in Phase three and expanded Phase two studies. We hope to see these drugs come to the clinic real soon for our patients. Another target where we've seen some exciting data are patients with her two mutated lung cancer. These mutations are seen in about 1% of non small cell lung cancer patients. We don't have any approved therapies. Chemo is our go to for this patient population. At Escort 2020 we saw very promising results with this antibody drug conjugate called Trust Us. A Mob directs the camp. Those of you who treat breast cancer may be aware of this drug. Since it's approved in breast cancer, this antibody drug conjugate targets her two. And in a single arm trial of approximately 50 patients, this drug had an efficacy results. With the response rate of 62% for her to mutated lung cancer, the median PFS was quite impressive at 14 months. This has given at 6.4 mg per kg ivy every three weeks. So another promising drug, one of the toxicities with this drug is interstitial lung disease. That can happen in 10 to 15% of the patients. That's something to be monitored for. This is being studied in larger cohorts of patients. Another target where we have seen some recent data or patients with G F R in search in 20 mutations. These are very difficult mutation to treat. There are two drugs to keep your eyes out, for one is an orally administered called mobile. Certain Mobile certainly has response rates of about 25% to 35% in this patient population, with the median PFS of approximately 6.5 months. The other drug is given to map, which is a monoclonal antibody that targets E G F R and Met. And this drug has response rate of about 40% in this group of patients. So both of them are being developed for E g fr insertion 20 mutations, and we look forward to hearing more about these drugs in the next several months to a year, so In conclusion, I want to re finish by saying that molecular testing should be performed for all patients with non squamous non small cell lung cancer. We should wait for the results before starting therapy. If the patient is clinically unstable, start chemo alone, not chemo plus immunotherapy. We know the targeted therapy improves outcomes for patients with at least seven different molecular targets in lung adenocarcinoma. So for those patients, targeted therapy should be the preferred frontline therapy. And for patients who do not have driver mutation for PD L one high patients give them PT one in a better alone are PD L one inhibitors alone for patients with low PD L one of negative PD L one. We could either use chemo plus PT one inhibition or the combination of BP and Nova Lima. With that, I'm going to stop, and I'll be happy to answer your questions during the panel discussion. Thank you so much.