How to Treat Small Cell Lung Cancer (SCLC) – Treatment Algorithm with Dr. Jacob Sands

[MUSIC] We are the oncology brothers. >> Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossein here with my brother in your co-host, Rohit Gossein. With our goal of keeping you, our fellow community oncologist up to date with everything happening in the world of cancer, today we're diving into the current treatment algorithm for small cell lung cancer. This still remains an aggressive disease, but thankfully over the past few years, we've seen some meaningful advances. Be it Adriatic study with Dervalumab in limited stage, or I am forte with a Tizal urbancted and now being the standard of care as maintenance and extensive stage, and then to Latumab thereafter as second line treatment option. There's a lot to cover here and for less we're excited to welcome back Dr. Jacob Sands, a thoracic medical oncologist from Dana Farber Cancer Institute. Jacob, thank you so much for joining us. >> Thank you. I always love joining you guys. >> Jacob, welcome. We got quite a bit to cover here. So let's dive right in as Rahul stated that it is an aggressive disease, but we are lucky to see few advances that we still have quite a bit to go here. Focusing on early disease, which is rather rare, but thanks to our lung cancer screening, we are able to detect some of these tumors much earlier, where the treatment essentially is surgery upfront, followed by adjuvant chemo. And Jacob, you have an ongoing trial here with the addition of immunotherapy in this arena. So if you could please help us out with potentially resectable small cell lung cancer your approach here. >> Yeah, thank you so much for calling out. We have an Alliance Foundation trial. It's AFT 61. This is something Jeff Yang is a thoracic surgeon at Mass General and I are collaborating in this trial. This will be open or is now opening at about 15 sites across the country for those who undergo surgical resection to then get single arm platinum atopicide plus Dervalumab. It's a year up to Valumab. But I'd say right now as a standard of care, those who have a solitary lung nodule, I think it's really worth doing surgical resection. And part of that is the pathology. I mean, one will see whether there are lymph nodes involved, but also the pathology of the primary. And I have had some where they came out and the final pathology ended up not being small cell lung cancer. And so the treatment algorithm is really different. In those who undergo surgical resection who have a small cell that's resected, all should be getting platinum atopicide for four cycles as adjuvant therapy. You know, be it your trial or all disease sites. We continue to see that immunotherapy continues to move earlier and earlier. But again, resectable disease, small cell lung cancer is still a rare entity. Let's shift gears to something a little more common. Limited stage where we're relying on concurrent chemo radiation. And now we have data for Dervalumab from Adriatic Study. The resulted in improved overall survival. Here IO is for total of two years. Jacob, can you touch into data here? And importantly, what's your practice around PCI? Who do you consider PCI for? And if so, what's the timing's like in relationship to immunotherapy? Yeah, so I'll come back to the PCI. That is a murky or question to start out with the data that we have from Adriatic. So concurrent chemo radiation, and fundamental percent of radiation, then followed by two years of Dervalumab. That's the Adriatic Study showed a seven and a half month improvement in the median progression free survival. 22 and a half month improvement in median overall survival. These are astonishing numbers. Now, part of this is that in the limited stage setting, those curves are not as steep to begin with. It tends to be a little closer to that 50% line, the median. So those numbers sound overwhelmingly better than Caspian, which was metastatic small cell lung cancer, including Dervalumab in that setting. That being said, if you look at the curves next to each other, the curves from Adriatic look very similar to what we see from Caspian in the way that they separate out. And I think what we're seeing from Adriatic is just a validation of the efficacy of Dervalumab in the setting of small cell lung cancer. Now, I expected that from the Attesalismab trials as well, which we did not see those curves do not separate out at all in Attesalismab, although it's part of the metastatic paradigm, it is not something that has any data to suggest efficacy given that the curves overlap in the limited stage setting. So very clearly, the standard of care in limited stage now that undergoes chemo-radiation is two years of Dervalumab. Now, the reason for two years is because the vast majority of patients that have recurrence have it within those two years. And I think that's fairly good justification is one year enough as a common question. You know, we don't know, but if it's two years of therapy, then at the time of recurrence, assuming patient has recurrence, it's likely within that Dervalumab time frame. And I think at that point, you'd go on to something else. With the exception being intra-cranial metastases or kind of a solitary site of recurrence that you can radiate or ablate or asact or, you know, however it is, then I may continue the Dervalumab in select cases, especially for intra-cranial only, which gets to the challenging question of what about PCI? Now, you know, PCI in the extensive stage setting, we've really leaned away from. There was early data that showed an overall survival benefit to PCI in the limited and extensive stage settings. But we then saw a trial out of Japan in 2017 that showed Q3 month MRI brain if anything had a trending better survival than those who got PCI. And the big difference between that trial and the prior ones is an MRI brain at baseline and then ongoing MRI brain monitoring. We don't have data from the limited stage setting, but I will tell you that for me, what that trial demonstrated in the extensive stage setting is that our data from before was flawed. And so I recognize that now we don't have other data. And I hear people say, "Well, we don't have the updated data." So the data we have showed survival, I say, "Well, I think we've seen a demonstration that that data was already flawed." So I really look forward to having the Maverick data. I'm hoping we'll have that this year. I've heard that they changed the primary endpoint from overall survival to more of a tolerability toxicity. I can't confirm that, but I think at a minimum we'll see directionally what makes sense. Right now in the limited stage setting, I think it's harder to know what to do. But I do worry about, these are people we're treating with curative intent and decades out what's going to happen from a toxicity standpoint of radiating their brain. I worry about these kinds of things. One other thing I can add is that the Adriatic data that was reported out, they did report out subset data looking at those who got PCI and those who did not get PCI. And the data, those survival data, for those who got PCI looks better. And I've heard people talking about that as a reason to further reinforce doing PCI. And I just want to caution people that this is not randomized. The patients that are going to get PCI are generally going to be younger patients with fewer common abilities. And I think when we're looking at the comparing these two, I would expect that population to do better from a survival standpoint in younger population with fewer common abilities. So I caution people against drawing any conclusions from these PCI subgroups as well. So, you know, limited stage. Frankly, I am maybe more on the skeptical side and leaning away from PCI, but I really look forward to having some data. Well, thanks for summarizing that, Jacob. And I've run into that dilemma. Should I give PCI versus not, especially in that young population, based on that subset that you're talking about. But at the end of the day, my preference is still MRI surveillance because the whole brain radiation side effects, especially the quality of life is when we have cured this disease potentially. And what you stated was the Adriatic 22 months of Delta, which are available after a chemo-radiation therapy, is significant as a result. This is, in fact, our new standard of care. Moving along, in two extensive stage, which is, unfortunately, a common scenario that we deal with. Where we started off was chemotherapy initially. Then we started adding a Tizzle-izumab or Dervaulumab, that's the immunotherapy. And now we have something even better. I am forte. After a carbonyl toposide, a Tizzle-izumab for four cycles, maintenance of a Tizzle with lurbanectidan, which is demonstrated rather an overall survival benefit and is, in fact, the new standard of care. On disease progression, we rely in second line with Tarlatumab. Jacob, thoughts around extensive stage, small cell lung cancers. Well, it's exciting that there's so much to discuss. And maybe first, I'll just say that there is more happening right now in small cell lung cancer as far as promising drugs available in clinical trials than the culmination of everything up to this point. And that's just to highlight that clinical trials, consideration are very important for patients with small cell lung cancer, given how much is going on in the field right now. But you're highlighting some big ones recently. Now, the Mforte data, I think, is a complicated story, clearly positive in progression-free survival, clearly positive in overall survival. And there's a hypothesis about synergy with a PDL-1 inhibitor and lurbanectidan, based upon the efficacy of lurbanectidan or the effects of lurbanectidan within the tumor microenvironment. It clears out tumor-associated macrophages, which can be stimulatory cells to the tumor, and Vajaf, and vascularization, by clearing those cells out. The hypothesis being that we're allowing for more infiltration of immune cells that are going to fight the cancer. Now if we were to see synergy from the combination my hope would be in the demonstration of synergy, would be in the tail of the curve I would expect to see patients that we're not going to benefit from immunotherapy, actually benefiting from immunotherapy. A separation in the tail of the curves that extends out like what we see from those immunotherapy long-term responders. The initial data from M4 to show the progression of resurrival curves came together in the tails, but the overall survival curves stayed separated. The updated data now shows the overall survival data curves coming together as well. I don't think we're seeing synergy from this combination, although we're certainly seeing efficacy in those months after finishing the platinum atopicide, likely the patients that we're not going to benefit from the checkpoint inhibitor now getting kind of an early cytotoxic and early second line in there. Now this was a global trial. I think the bigger question is now in a US population where they have access to urban actin, let alone now tarlottima, which is a whole different paradigm, would those overall survival curves, what would those look like in a US population? We don't have a lot of data on this. There weren't a ton of patients enrolled in the US, only 9% of patients that were enrolled in the control arm ended up getting urban actin as a second line. So there is a toxicity that goes along with urban actin, albeit one in which I think for many it's quite manageable. It's a toxicity profile most oncologists are very familiar with. It's mostly siteopaneous, some fatigue, some nausea, those are usually low grade over a couple days. And if that's all then that's fine. I think someone who tolerated platyematoposide well and is highly motivated and come in every three weeks for a combination of lurbia tezzo, this can be a very good option for them. I would caution though, and someone who's been on prolonged treatment, I would make sure that they continue to be trial eligible, even if they're not going to go on trials. Maintain their siteopenia levels, don't let those become an issue. If you want to maintain their performance status level and their labs and such for second line therapy. Now to jump to Delphi 304 that you mentioned, tarlottima and the second line, tarlottima beat chemotherapy in every way, it beat it in progression free survival and overall survival. Progression free survival was not overwhelming in the median, but the tail of the curve, 20% of the disease control at a year as compared to just 4% on the chemotherapy arm. So clearly separates out in a way like we see with the immunotherapy agents, less of a toxicity profile, also better symptom improvement. So tarlottima beat chemo in four out of four ways. And to further highlight this, this is the only trial in the second line setting of small cell lung cancer that is a positive trial randomized to a control arm that is therapeutic and in fact the only randomized trial otherwise that's positive was topotican PO versus best supportive care and it wasn't as positive. So you know, topotican IV got FDA approved based upon a study in which the curves with CAV completely overlap. Wow, there's quite a bit to unpack here. Starting off with I am forte story, you know adding that lurbanectid and maintenance, the median overall survival here is 13.2 months versus 10.6 months with hazard ratio of 0.73. This again is improved overall survival, but we have strong data not just for small cell lung cancer, but this ends up being a bigger problem here, but across the disease sites, a lot of our patients don't see that second third line treatment option. So perhaps putting this as maintenance is likely the way to go to make sure they're getting exposed to this activation. So with lurbanectid and maintenance, we have to add growth factors here. We also have trial cyclophen this space to help with cell counts, but I've not used that heavily in my practice. Jacob, do you use this in your practice at all? I do. And you know, trial cyclophen has been wonderful at preventing or decreasing the amount of cytophenias. So not just neutropenia, but anemia and thrombocytopenia. Now it's FDA approved with platinum atopicide and with topotican. I don't really use topotican. I use a rinatecan instead. Jared Wise from UNC is doing a study with lurbanectidin, including trillociclet. And I think that's a great one. There are also antibody drug conjugates in development that have cytophenias that I think could probably benefit from the inclusion of trillociclet. I don't use trillociclet for everybody, but in those who are getting platinum atopicide, if I have any concerns about neutropenia, let alone anemia thrombocytopenia, if I, in a setting where I would start GCSF, I put them on trillociclet instead because it controls all cell counts. One of the things Jared Wise has shown with trillociclet in patient-reported outcomes is not just reduced degrees of cytophenias, but also less fatigue. And I think what it's made me appreciate is that there is fatigue from the cytotoxics, of course, but there also seems to be a degree of fatigue from anemia. Even in patients not undergoing transfusions where it doesn't get to that point, if the more there's anemia, the more likely this is kind of adding to their fatigue. And I think that's what we're seeing from these patient-reported outcomes studies. And another reason to consider using trillociclet. Absolutely. You know, maybe I just need to take a step back and re-evaluate that right particular patient where I can start using this. But to close up, the topic of I am forte, to me, this is now that first line treatment for all extensive stage muscle-on-cancer, unless someone is frail. And then for a second line, we have to relax my back. Before we close off the topic with lurbianotizo completely, some of the nuances that we have encountered is if the patient was already started on derva-based regimen, can you combine derva with lurbianectidin? At least for my practice, I have switched them to otizzo plus lurbianectidin, though I don't see any major difference amongst the immunotherapy arms, but at the end of the day, I just want to be purest, and I know that's what people have been doing. I'm not sure what your practice at Rahul is, and Jacob, I'd like to get that input. I think that's valid. I see these as interchangeable derva-natezo. I have heard individuals that had issues with insurance coverage in that way, where they required a tezo. I've heard others that were able to get it approved with derva. And so I don't have a strong preference. Right, because of the data, I'm now starting off with kimo-tizzo mostly, and then just sticking with that to zom and then continuing with lurbianectidin. Okay, coming back to second line, here we have terlatumab after getting kimo-io and lurbianectidin. Yes, lurbianectidin is also available in second line, but again, majority are getting this up front maintenance settings now. For terlatumab, that median overall survival is 13.6 months versus 8.3 months with hazard ratio of 0.6.0. The adoption of this has been low because of the coordination. But given OS, we need to make sure our patients are getting exposed to this. You know, in community settings, we have bunch of bispec effects that we're using for hemo-lagnancies anyhow. So we need to get comfortable around this. Jacob, any piece of advice on how you coordinate this on your rent? Well, first of all, I have a handful of patients that came to me because their oncologists told them hospice is all they've got and recommended against any other treatments. I have a patient who is very poor functional status. Liver full of disease, she had gotten every regimen and terlatumab got FDA approved, kind of right when she needed it. But I ended up treating her. She's now a year and a half into her treatment with ongoing disease control. That's not something we're seeing much from these cytotoxic regimens. So it's not just the median improvements, it's a tale of the curve that is overwhelming. Now for some people, I recognize that you're not really hospital based. And so trying to then coordinate an admission for treatment is a challenge. And so hopefully you can find a partner site that can start therapy. It's the first two doses where people can have CRS. And most of those are grade one. They get Tylenol, they're fine and they go home. Those two's happen and those need to be managed and 1% grade three in the trials that we've seen consistently happen as well. And obviously those need to be managed. Once you get past that though, everyone should be able to give terlatumab in the outpatient setting once you get past cycle one, for example. And so these collaborations are of real value. Now I love seeing patients that come in to consider starting terlatumab because it allows me to highlight for them the clinical trials options. Now for some people it's a long trip and really to be able to then get terlatumab closer to home is better for them. And so we arrange for that. And then as a last comment, Delphi 305, we may see data this year or next year. This is terlatumab in the maintenance setting. Jacob, thanks so much for summarizing that data. I just want to read right that this is or else survival benefit. And is one of the few advancements that we are seeing in this disease space, along with limited stage with terlatumab in consolidation setting and lure benactin in maintenance front line option for extensive stage with a tizalismab. One thing I'd also like to add is role of consolidation radiation, especially in that disease state where we are seeing excellent response with upfront treatment. And here as well for C&S disease, I'm not doing whole brain radiation therapy. Continuous MRI surveillance is rather the key because again, the side-effect profile of whole brain radiation therapy. For progressive disease, received chemotherapy, immunotherapy with the lower-beenected inmates. The second line option is to our Latin map. After exhausting all that, the choice is single-agent chemo or re-challenge with platinum or clinical trials, which is always the right answer. Jacob, we have covered quite a bit thank you so much for walking us through your treatment approach with regards to small cell lung cancer. On RN, let's go for a quick recap from today's discussion. In today's treatment algorithm episode with Dr. Jacob Sans, we covered small cell lung cancer. In limited stage disease, concurrent chemo-radiation followed by dervalumab consolidation for up to two years is now the standard of care based off adriotic study, where we've seen the median overall survival roughly of 56 months with dervalumab versus 33 months. The role of PCI here still remains a further bait, while we await results from the maverick trial to see if surveillance brain MRI is good enough. For all of that, key takeaways in extensive stage? Right, Rahul. For extensive stage, we started out with the initial treatment option that is carbol atopicide and atysolizumab in induction for four cycles, followed by atysolizumab lurbanectidan and maintenance option. This is based on I'm for taste study. What we are seeing with this is PFS and also overall survival benefit with overall survival has a ratio of 0.73 and don't forget the growth factors tied up with lurbanectidan. And then in second line setting, we have to her Latumab based on delphi 304 where we again have overall survival data that is 13.6 months versus 8.3 months with chemotherapy. For small cell lung cancer, it is certainly a terrible disease, but these advances are giving our patients more time and more hope. Thank you for tuning in. Make sure to check out our other treatment algorithms, FDA approval discussions and conference highlights. We are the oncology brothers.