Chapters Transcript Video Second Line Treatment Options for Relapsed/Refractory Small Cell Lung Cancer Back to Symposium We are going to move on to our next talk. This is going to be by Doctor Part Desai who is an assistant professor at the Department of Hematology and Oncology at Fox Chase Cancer Center. Uh Doctor Desai is going to talk about second line treatment options for relapse, a fracture, a small cell. This is an area where we have asked him to concentrate on at Fox Chase. Obviously, because of all the advancements that we see in this disease and all the clinical trials. Doctor Deai, thank you for the organizers. And so um just as a caution, uh I'm gonna be fast because that's how small cell lung cancer moves and my trucks are going to be small. All right. So I don't have any relevant disclosures. So as you can see from Dr Chang's slide with the Im Power 133 relapse in small cell, lung cancer is inevitable. You can see that at this moment when we cross for extensive state disease, 12 months, more than 85% of patients even with the current standard of care, which is chemo immunotherapy relapse. And I'm not gonna take the thunder away from doctor treat. But you know, basically more than 50% for patients with limited state small cell lung cancer who get chemo radiation and now have started getting immunotherapy in the maintenance phase. So this is an important concept that you have seen, but I just want to walk you through this, the idea of platinum free interval. This was born back in 19 nineties where the two drugs were carboplatin and oppo or Irene not T can and had just come out compared to C and had been winners and what they had identified or they were looking clinically were two distinct biolog of SCLC. And what it means is that after you complete your chemo doublet, how soon the small cell recurs. And that tells a lot about the biology of the disease in that person. And there are sort of two broad patterns but it's not a strict number. It's sort of a continuum. But that definition has changed now because now we do not sit and wait after giving induction treatment for most patients, we give immunotherapy after chemotherapy in extensive stage or limited state. So what's that ideal number? Well, we don't know this, I refer you to this paper. They come up with some interesting statistics and come up that actually our number was false to begin with and the new number is something different. This should be your homework. Um anyway, so quickly going through this. So these are our old horses to and then relatively new ed in to put five day infusion infusion have to start on Mondays. This has been approved since 1996 and is still on the on the FD approval list. And then compared is the more recent accelerated approval which has not been approved yet in its full is which is one day infusion relatively easier to infuse. And this is the top and data comes from a randomized study done in 1996. And then some of the other confirmatory studies after that, but essentially, it's driven by it was driven, it was comparing against the previous standard of care, which was C A triplet chemotherapy combination. And there was not much difference in terms of toxicity profiles, but there was more difference in in the symptom improvement. And if you can see that the overall response rates were pretty similar in that era, they acted in approval ideally comes from from a single arm study where it was tested and they saw that the response rate were around 35% more. So for platinum free interval disease, which was more than 90 days, median duration of response of 5.3 months, but very well tolerated, relatively low rates of grade 34 neutropenia and other bone marrow toxicities were less prominent and more importantly, nausea and MSs was not a major issue with lectin. So what do you choose between lectin and topo can in the second line setting? Well, we don't currently have results from the Randomized Lagoon trial. But this is a sort of a T analysis done on a field study with L Acted in combined with doctor in the Atlantis trial, which unfortunately didn't meet its primary end point. But the data from the top of that study was compared with a basket study looking at led and this was a patient to patient matched comparison and seems like the indicators are that led in probably doing better in terms of overall survival and also maybe a little better in terms of the response rate. And we know that it's it's a better tolerated drug. So these results, hopefully we should have the results of lenine and it's being tested with full dose Larin versus reduced dose Larin in combining with another topoisomerase inhibitor versus just a topoisomerase inhibitor. And it's also enrolling patients with really platinum free interval more than 30 days or it will include patients with platinum refractory disease, which is actually a more unmet need. So what about plot platinum doublet three challenge? This is a question that comes up a lot of times in relapse small cell lung cancer. We've been practicing this for many years. Essentially, it's giving the same drug that has worked in the past. If the patient's disease ever occurred after 90 days of the of the prior treatment, the data to this comes from, you know, there are, there are several post talk or retrospective studies done but the best data actually comes from the study in France that looked at combined, you know, randomizing this, this group, this this this treatment versus oral topo. And, and what they saw is that, you know, there is definitely an improvement in progression pres survival, but there's not much improvement in the overall survival. So we don't know what to choose there. So there has been limited progress for relapse, small cell lung cancer. You can see non small cell lung cancer. There's a plethora of agents driven by the genomic boost and our understanding of the biology of disease at the genomic level. But with small cell lung cancer, we had an approval back in 1996 we had a couple of accelerated approvals that got squashed, especially with the integration of immunotherapy in upfront setting. And then we have been acted in currently as an accelerated approval approved drug. However, we have this new drug in the town which is a map. So this was based on the D 5301 study. But the approval came this year in May 2016 where the accelerated approval was granted to LA based on excellent responses seen in the 5301 study. So what is so T is ad L three or delta like li and three targeting B specific T cell engage. So essentially what it is is it's a small molecule which brings CD three positive T cells close to small cell lung cancer cells. It also is a modern construct of T cell engages where it has albumin on it. And so it's allowed to stay in the system for a long period of time, avoiding a continuous infusion and you can infuse it every 15 days as opposed to the older bites which are used in leukemia such as well. Good news in SCLC is that DL three is almost ubiquitously expressed in this data from C bio portal as compared to other cancers. DL three is not expressed in most of the healthy adult normal cells, other than the rare pulmonary neuroendocrine cells and some cerebellar cells that we know of. So this was the D 5301. This is the, this is the design, how the, how the tab is now given. So it's given in a step up dosing fashion mainly to look out for the serious side effect, which I'm going to talk about in the next few slides is that the first we give the 1 mg dose on day one, then we give the 10 mg dose, which is the step up dose on day eight and we give the 10 mg dose on on the day 15. And then we sort of give this in a biweekly fashion until progression or unacceptable toxicity. So in this study, two doses were evaluated and the 10 mg dose seems to be doing much better overall response rates of 40% unprecedented median duration of response of 9.7 months, medium time to response is very quick, very fast, almost after the one's first cycle. And then you can see the spider plots, those who respond, they responded for a long period of time. But there are a group of patients that either do not respond and have have stable disease for some period of time. Um The more promising findings and this is early evidence is that this drug works irrespective of the platinum sensitivity, even even with the newer definitions. And it also seems to be working with patients with liver metastasis at baseline, which we think is a very poor prognostic indicator of small cell lung cancer along with brain metastasis. But the big problem that we are sort of learning and I think hopefully as we move forward with these agents and this type of agents is managing these unique side effects that our rheumatology colleagues know how to manage very well, which is cytokine release syndrome and neurotoxicity. What you can see from this study is most of the cytokine release syndromes were grade one and grade two. I don't want to downplay the cytokine release syndrome. Most of the grade two CRS means that those are hypertension that needs fluids, those are fevers that needs to be managed and monitored and they can sometimes rarely go to grade three. But you can see that the incidents of grade three CRS were rare and most of the grade one, grade two CRS occurred during the first two doses, which is the 1 mg dose and 10 mg dose. The median onset of CRS is about 13 hours post infusion. So it's predictable. And so that's why the FDA has a certain guidance which I'll come across, but the neurotoxicity could be delayed. So that is seen after the first dose, you know, probably at the end of the first cycle. And so that is a little bit, you know, it's a slew like symptom that we have to catch and we need to make sure that the patients not suffering from that, which could be a big issue in small cell lung cancer because there is also the competing idea of having brain mets or received prior radiation. The another interesting side effect that, you know, we sort of learning is neutropenia, which we did not expect could be due to the cytokine storm, but we don't know the exact reason for that and then some transaminitis. So the FDA mandate is very specific monitoring ideas, sort of specific and not so specific as I would, you know, satire out there. So they say that, you know, patients who receive the first two doses need to be monitored for 24 to 48 hours in an appropriate health care setting. And there's no such definition of what appropriate health care setting is where a lot of issues are coming up in us trying to integrate this drug into our health care systems and the insurance is paying for it or who's going to pay for it actually. So the question is, is superior to other agents for relapse? I forgot to tell you. But in 301, it was studied after two lines of treatment. So there is a confirmatory study going on which I'll talk about. But is it going to be superior than other agents in rapt CLC? Well, if you see my commentary that we just published last month from superficial data, just comparing it indirectly, overall response rates and duration of response, it seems like the winner. It's the one on the most on the right hand corner as compared to led in to. But there are challenges to its delivery. The increasing proportion of patients with small cell lung cancer being aggregated in rural suburban area because of increased smoking or non decreasing smoking incidence. Is there the requirement for post treatment monitoring? What sort of centers you need to manage them? And the and the and the rare fatal side effects that can happen? The neurotoxicity, how are we going to understand that or integrate into our daily practice? There's always, there's always a scheme or chance for biomarker optimization. And although is born out of a biomarker driven approach, but we know that not all patients respond to it. So what are the factors that predict its response versus not, there could be more than tumor, there could be patient factors and disease related factors and what are the potential organisms of resistance? So these are all important questions. D 5304 is actually trying to confirm las place in second line setting where it's a randomized open label phase three study at multiple centers. Looking at the 10 mg dose of tab versus sort of the physicians choice standard of care which is led in and or or Mr which is practiced more in Japan. Um There are some very exciting potential agents in the pipeline. So there is this B seven H three or CD 276 targeting ADC. There are in fact a couple of compounds and this was presented in the world lung, very exciting response rates with higher dose of this ADC which is around 3434 to 54%. And then the main side effects noticed are gastrointestinal and myelosuppression. Someone a keen to the to the to the de direct and derivative. There is this other well known tr 280 see a drop two is expressed in some of the small cell lung cancer cells. And there is some exciting data, early data showing that single agent drop 2 may, may be effective in in in treated or relapse small cell lung cancer with almost 40% response rates and there were no safety signals noted. So in conclusion, I would say that small cell lung cancer is fatal, but there is hope and at this moment, when I see a patient with relapse small cell lung cancer, I ask myself these questions. Is there an active clinical trial that I can enroll the patient in to? Is there a recent CNS imaging done? Because that's a big determinant of how we are going to approach small cell lung cancer, especially for the community oncologist where this might get lost in the whole scheme of things. What was the platinum doublet free inter what was the platinum for? What's the biology of the small cell lung cancer? From the clinical phenotype that we know, is it go progressive? Although that question is not very well answered, you know, will zipping a lesion with SPRT help. Early evidence shows that it may not because SCC is really, you know, a metastatic disease to begin with. And I didn't cover that area and then what's the performance status and the bone marrow function? Because at this moment, we know that it's essentially incurable disease and and then there should be realistic expectations about that as Dr Chang really mentioned, but it seems like is giving us new hope. And so are these other agents and I would sort of fit them in, into, into, into any point at this moment until we get confirmatory trials. So with that, I like to thank you for the opportunity. Created by Related Presenters Parth A. Desai, MBBS, MD Assistant Professor, Department of Hematology/Oncology,Fox Chase Cancer Center
