 What ongoing research are you excited about in this setting?

First is the role of immunotherapy. Because we see it working, we feel that we have maximized its effects. The clinical trials are looking into more agents that compare with better outcomes. At the same time, we have been finding other targets like the DLL3. There is not really a successful clinical trial on that, but maybe this is a target that we can take up front in a different way. At the same time, we have more clinical trials coming that focus on the genetic defects of small cell lung cancer, like the PARP inhibitors. We’ll be looking, so we’ll need more preclinical data to identify more biomarkers and be able to have more targeted therapies because targeted therapies are what help us with the adenocarcinomas.

 Taofeek, what are you excited about that’s coming down the pipeline?

The field, as a whole, is going to benefit from these large, randomized trials where samples are collected. The more we look, the more likely we are to find something, even if we don’t know what we’re looking for. Having said that, the ongoing trials of immunotherapy approaches in limited-stage disease is very exciting. I look forward to seeing those results, and I’m hopeful that they will look like what we’ve seen with locally advanced non–small cell lung cancer. The other approaches are, as Konstans indicated, the addition of targeted therapy to immunotherapy and to radiation in the maintenance setting for extensive-stage disease, as well as the anti-DLL3 strategy for the relapse setting. The initial foray with the antibody-drug conjugate was not very successful, but we now have 2 bispecific T-cell–engaging antibodies in clinical testing. Those look really promising; we’ll see where they lead us. Finally, understanding the certainty of small-cell subtypes is one thing that will really help drive the field forward. We have the f4 main subtypes: ASCL1, NEUROD1, POU2F3, and YAP1 subtypes of small cell. We are beginning to see that these different subtypes have different phenotypes, and that could help us try to match the subtype with specific treatment approaches. I’m really excited by that opportunity going forward.

 Awesome. Thank you both for being here. This has been an excellent discussion. We hope you found the information to be valuable to your clinical practice, and thank you for watching 

Videos

Ongoing Research in Extensive-Stage Small Cell Lung Cancer

Our frontline options are improving, but unfortunately, for most of our patients, the vast majority will still progress after frontline therapy. What treatment options do you consider with a patient progressing after platinum with immunotherapy, or platinum etoposide with immunotherapy?

 We’re all excited about the efficacy impact, the survival impact, of adding immunotherapy to chemotherapy in the frontline. We have a new frontline regimen. Whatever we used to consider our second-line regimen is no longer as meaningful as it used to be because our frontline regimen has changed. Whatever we’re doing in the second-line, third-line salvage setting is up in the air. Before the IMpower133 and CASPIAN trials came on board, our approach had always been that if the patient tolerated the frontline chemotherapy well and had very durable duration of response, go back and retreat them. Now we have 2 randomized trials showing that re-treatment with platinum doublet, in terms of overall survival, is probably no better than using topotecan, and that could also come at the expense of perhaps slightly higher hematologic toxicity rates. If topotecan is something that none of us wants to use to start, and our re-treatment with platinum doublet is no better, that area becomes wide open.

In the contemporary setting where we’ve treated patients with chemotherapy-immunotherapy, we’ve had only 1 newly approved drug, which is lurbinectedin. This had accelerated approval and a limited data set, and the majority of those patients did not get chemotherapy-immunotherapy. A small number of the patients, maybe about 20% or so, got exposed to immunotherapy before going on the lurbinectedin trial. I put that at the back of my mind when I decide what to do for patients.

What factors do I consider? How quickly is the patient progressing following chemotherapy-immunotherapy? If somebody is progressing during the induction phase, that is a very bad sign. That means that it doesn’t matter what salvage option you want to use because it’s probably not likely to work. That’s where I would bring forward the discussion about quality of life and try something to see if it helps. If somebody went through the induction well and stayed on the immunotherapy for a while, then you have some options to explore. Lurbinectedin could be an option there. You could also think of other strategies that may be immunotherapy-based, but that would be part of a clinical trial because the single-agent approval that we have for immunotherapy now is more in the third-line, so the patient would expect to have failed frontline and another agent. Those don’t come into the picture until you get into the third line.

When we look at the lurbinectedin data, we know that patients who did well with platinum doublet chemotherapy also did better with lurbinectedin. There’s something to be said for platinum sensitivity. You’re twice as likely to respond if you responded to platinum doublet. For those patients, my inclination would be that if you responded well to platinum doublet and I have to do something in the second line, I would go with lurbinectedin. If the patient did not respond well, the response rate we see with lurbinectedin is similar to what you would expect with any other cytotoxic agent we’ve used based on limited phase 2—even topotecan—with single-digit to approximately 20% to 22% response rate.

Overall, is the patient platinum sensitive or platinum resistant? If they are platinum sensitive, I would probably lean more toward lurbinectedin. If they’re platinum resistant, then I would look at patient characteristics and discuss goal of care. If the patient still wants to give it a shot, lurbinectedin would still be an option. For that group of patients, I would look toward new approaches with clinical trials to see if there’s something that would be better than what we currently have.

 Konstans, is your practice any different? Have you had any personal experience with lurbinectedin so far?

 We have been able to use it in many of our patients, but it’s too early. It’s seems to be more well tolerated than topotecan. Because the patients did not progress in the clinical trial, I used it with patients who were already failing with topotecan. I could see a difference in the way they could tolerate it. Lurbinectedin is becoming very strong in the second line for patients who are good candidates, as Taofeek said.

The only question is, what do we do with newer therapy? Only clinical trials will be able to answer that. We have decided that it is so great in the first line, but when we’re thinking about progressing, we forget it until we remember it again in the third line. Clinical trials will investigate whether continuing to have the backbone of immunotherapy would make any difference, and that would be a good question for the future. Topotecan will have a role for patients who might be progressing with lurbinectedin and have a good performance status. I’m looking forward to combinations with immunotherapy for these agents that would make a difference.

 I completely agree with you that clinical trials are needed to determine how we use immunotherapy in people who progress on frontline chemotherapy-immunotherapy. As part of standard of care, do you think there’s any role for continuation of immunotherapy in someone who has progressed on it?

 I’m a little biased because I believe in the backbone of immunotherapy. … Have we done it? Yes. Outside the clinical trial, it wouldn’t be a good way to know that you have data. We have a trial where we’re talking about second options of chemotherapy while we continue the immunotherapy. We can follow this data to see, first, if it’s safe, and second, if we can get some signal from responses. It’s an amazing time; many things are coming for small cell lung cancer.

 That segues nicely into our next question.

Treatment After Progression on Front-Line Therapy in Extensive-Stage Small Cell Lung Cancer

We’re fortunate to have multiple positive trials in small cell lung cancer. Keeping these trials and others in mind, what’s your standard first-line approach?

At our institution, we have both the CASPIAN regimen and IMpower133, and it is a matter of being more flexible. If you want to do cisplatin, you can use the CASPIAN, but otherwise, I find that they are clinically equivalent. We’ve heard about palliative meaning of the treatment of this disease, but we now have the patient-reported outcomes from both studies published, one by Dr Aaron Mansfield and the other by Dr Jonathan Goldman. Both showed that patient-reported outcomes are very good with the addition of the immunotherapy and without compromising the quality of life. We have very strong data from patient-reported outcomes that both regimens are very good.

I have tried to scrutinize my colleagues and point out my own differences, but I don’t think we can find a lot of differences. The message is quite strong, that additional immunotherapy in our standard platinum etoposide improves outcomes.

I would echo that, adding that this is my first-line treatment option for most of my patients. The only reason I wouldn’t use immunotherapy is if there are specific contraindications to immunotherapy or if the patient is not able to tolerate chemotherapy itself, and I know that just using immunotherapy is not likely to help. Some of the challenges that we currently face are like what we have for non–small cell lung cancer; we don’t have any reliable biomarker to help us identify patients. I don’t rely on testing for PD-L1 or tumor mutational burden to make the decision to use immunotherapy. The studies were not designed that way, and the analysis was not affected by PD-L1 or tumor mutational burden. I consider this to be low-yield, low-impact exploratory analysis.

I still get patients involved in the conversation the way we did when we had only chemotherapy. Now that we’re adding immunotherapy to the mix, we talk about the potential adverse effects of not only chemotherapy but also immunotherapy. Part of the initial hesitation with immunotherapy in small cell lung cancer was the concern of paraneoplastic syndrome getting reactivated by the use of checkpoint blockade. That has not been the case. From all the prospective trials we’ve seen, we haven’t seen any significant increase in the incidence of paraneoplastic syndrome when the chemotherapy with immunotherapy options were explored. Right now, this is my go-to regimen, chemotherapy plus immunotherapy.

 Have either of you used the CASPIAN regimen yet?

 Yes, I’ve used both. I’ve used both carboplatin/etoposide with durvalumab, and I’ve used carboplatin with etoposide and atezolizumab.

 Same here. Initially, when we would enroll patients, the dosing would be different because there was some different dosing of the immunotherapy during the maintenance period. With both atezolizumab and durvalumab being dosed every 4 weeks, the scheduling is exactly the same from the patients’ perspectives.

 As far as the choice of platinum agent, is that something that’s important to you in selecting a treatment?

 It’s important in a negative way, which is that we know cisplatin is more toxic than carboplatin. That was the rationale for developing carboplatin to start with. We also know that in big meta-analysis—looking at the impact of the choice of carboplatin vs cisplatin in small cell lung cancer—there was no impact on progression-free survival or overall survival. I don’t have any strong inclination to use cisplatin in the extensive-stage disease setting, where the goal of care is mostly improving quality of life longevity but not a cure. Having said that, I’ve always used cisplatin. I don’t have any issue with carboplatin; I wouldn’t begrudge them for using it. That’s where you have to bring the patient into the conversation. You’re more likely to find patients with contraindications to cisplatin than you will with carboplatin. One exception would be a patient with a lot of marrow involvement, where they already have significant cytopenias. Cisplatin might be easier to use in that population of patients in terms of hematologic toxicity.

 Exactly. I imagine you’re talking about the thrombocytopenia that we usually might see, and I totally agree. Coming from Europe, cisplatin is quite famous outside the United States. There is this flexibility to use it. In the United States, we all like carboplatin more.

 Is there any reason to believe that one regimen is better than the other?

 If we go strictly by the data, I don’t think we have much to choose from in terms of efficacy impact. The hazard ratios are in the same range, and the median overall survival estimate is in the same range. Even when you look at the long-term survivals, you’re still looking at about the same for both. Where you would go with one regimen vs the other would concern some of the nuances. Do you want to use cisplatin for this particular patient, in which case the CASPIAN data is the only one that has safety and efficacy data for that? For some of our patients with asymptomatic brain metastases, we know that the CASPIAN trial is one of the differentiating factors, that those patients were allowed on trial without getting brain radiation. If you have a patient with asymptomatic brain metastases and don’t want to wait for brain-directed therapy, then the CASPIAN trial has that additional benefit where they enrolled similar patients like that into the trial. To use it with atezolizumab would be extrapolating from other data sets because the IMpower133 trial required those patients to have the brain metastases treated before being in the trial.

Now that we can give both atezolizumab and durvalumab every 4 weeks, that becomes a moot point in terms of which agents to go with when talking about maintenance, which is the area where we focus on patient quality of life.

First-Line Approach for Treating Extensive-Stage Small Cell Lung Cancer

 Let’s move on to the second major trial that was presented, the CASPIAN trial, with durvalumab, etoposide, and platinum therapy plus or minus tremelimumab in extensive-stage small cell lung cancer. Would you mind discussing the design of that trial?

 The CASPIAN trial is similar to the IMpower133 trial in terms of concept and the end point of interest. This was a 3-arm trial trying to test the combination of checkpoint blockade using durvalumab or checkpoint blockade using durvalumab and tremelimumab, whether targeting both PD-L1 and CTLA4 to chemotherapy would be better than just giving chemotherapy alone. The initial plan and interim analysis of this study showed significant improvement in terms of the primary end point of overall survival and progression-free survival for the addition of durvalumab to chemotherapy. At that point, we knew 1 arm of the 3-arm trial was significantly better and improved the outcome when compared with chemotherapy. The data were not mature enough for the durvalumab/tremelimumab-plus-chemotherapy arm to be compared with the placebo arm.

Recently at the last ASCO [American Society of Clinical Oncology] Annual Meeting, we had the opportunity to see the full data set, and this helped us crystallize how important it is to add the immune checkpoint blockade to chemotherapy and, more importantly, how best to go about it—that maybe more is not going to be better. This was a randomized trial, 1:1:1 to the 3 arms of the study. Approximately 800 patients were enrolled, with about 260 patients in each arm of the trial. At the time of the data presented at ASCO, with follow-up of around 25 months, more than 80% of the data had matured. The initial report of durvalumab added to chemotherapy did better than chemotherapy was reconfirmed at this more mature data point. Hazard ratio was 0.75, indicating 25% reduction in risk of death with the addition of durvalumab to chemotherapy.

The median overall survival, which is generally not a good estimate of impact, was very favorable overall to the durvalumab-plus-chemotherapy arm—about 12.9 months vs 10.5 months. Looking at the long-term survival of the study is more important. You’re more likely to be a long-term survivor; 22% of those patients have been alive for about 2 years compared with those who had only chemotherapy, which was about 15% of the patients. These consistent data sets are similar to what we knew before about the addition of durvalumab.

What was new was the result of adding tremelimumab to the mix, so durvalumab plus tremelimumab plus chemotherapy. Three things stood out from this trial: One, by adding the tremelimumab to durvalumab and chemotherapy, there was increased toxicity; second, the increased toxicity was not insignificant because it also led to discontinuing treatment at a higher rate than when you only added durvalumab to chemotherapy; and finally, if the toxicity was improved or increased but still able to show better efficacy, they might say, “Maybe that’s a trade-off from increased toxicity and improved efficacy.” Unfortunately, that was not the result. The efficacy was not statistically significant. There was a trend toward improved overall survival for those patients who got durvalumab, tremelimumab, and chemotherapy compared with chemotherapy alone.

When we look at what the impact of the addition of immunotherapy to chemotherapy is—because we are able to deliver durvalumab along with chemotherapy more safely during that induction phase—you are able to realize the benefit. By adding tremelimumab into the mix, if you look at the median number of cycles of induction chemotherapy-immunotherapy that were delivered, it was about half of what you would do with durvalumab and chemotherapy alone. My own interpretation of the data is that what you ended up doing is not giving the patient the immunotherapy you’re trying to give; you also compromised the delivery of the chemotherapy itself, which, as we know it, is the more effective component of the regimen. That is why we did not see that early separation of the curves when we looked at the 4-drug regimen vs chemotherapy. With the 3-drug regimen of durvalumab plus chemotherapy vs chemotherapy alone, that curve separated much earlier at around 4 to 6 months. For durvalumab, tremelimumab, and chemotherapy, it did not separate until around 9 to 12 months. At this point in time, this would be our new standard of care for patients—that is, the addition of durvalumab to chemotherapy—just as we are already doing for atezolizumab with chemotherapy.

One minor point to make about the design of the CASPIAN trial compared with IMpower133 is that this allowed for the use of any platinum agent, carboplatin or cisplatin; for the IMpower133 trial, you are limited to just carboplatin. I don’t use cisplatin with my extensive-stage patients. For those practitioners who, for whatever reason—maybe clinical or personal preference—are still enamored with cisplatin for extensive-stage disease, this gives you the data set to support that the addition of immunotherapy to a cisplatin-containing regimen will be just as good as a carboplatin-containing regimen.

Results from the CASPIAN Trial for Extensive-Stage Small Cell Lung Cancer

You both mentioned a few trials. Let’s get into some of their specifics. Let’s talk about the IMpower133 trial with carboplatin, etoposide, and atezolizumab. Could you please go over the study design and the results from that trial?

 This is the first trial that made us all familiar with the combination of chemotherapy and immunotherapy. It was a double-blind, placebo-controlled phase 3 trial that compared carboplatin/etoposide with carboplatin/etoposide/atezolizumab. There were 4 cycles of the combination of chemotherapy and immunotherapy, followed with atezolizumab maintenance or placebo. When we had the first publication, there was a median follow-up of 13.9 months, and at this time, the overall survival was 12.3 months in the atezolizumab group vs 10.3 months in the placebo group. The hazard ratio for that was 0.7. The median progression-free survival in the same study was 5.2 months vs 4.3 months. The AUC [area under the curve] of carboplatin in this trial was 5 mg/mL/min, and they were including only treated brain metastases at this point.

That was amazing data for all of us, and they were confirmed by the update given by the investigator in 2019. Then, we had the median follow-up of about 23 months. The median overall survival remained the same, 12.3 vs 10.3 months. The hazard ratio was 0.76, and 13% more patients were alive in the atezolizumab group in both 12 and 18 months. Most recently, in ESMO [European Society for Medical Oncology] Virtual Congress 2020, we had a presentation of the characterization of the long-term survival, and there were more long-term survivals defined as surviving more than 18 months in the atezolizumab group compared with the placebo group. This is something that has to do with the discussion about immunotherapy. When they looked into the prognostic value of PD-L1 or TMB tumor mutation burden, they could not identify that. Even patients with a bad characteristic disease could be long-term survivors.

 That was the first large trial that was presented for extensive-stage small cell lung cancer with the combination of chemotherapy and immunotherapy.

Results from the IMpower133 Trial for Extensive-Stage Small Cell Lung Cancer

 Could you comment on the recent advances in extensive-stage small cell lung cancer, now with the availability of several checkpoint inhibitor/chemotherapy combinations? Is that your standard of care?

 The combination of immunotherapy and chemotherapy has become the standard of care for front-line therapy of extensive-stage disease, at least here in the United States, and I would say that will probably be the case all over the world soon. Not only do we have well-conducted prospective trials showing benefit of adding checkpoint inhibitors to chemotherapy, but now we’ve had 4 well-conducted trials showing definitive evidence that adding immunotherapy to chemotherapy is beneficial or, at worst, showing a trend because 1 of the studies did not meet the statistical significance.

In terms of the recent advances, we added only anti-CTLA4 to chemotherapy for the initial step, and that did not result in improved outcome. Adding anti–PD-L1, specifically the anti–PD-L1 inhibitors durvalumab and atezolizumab, to chemotherapy is now a standard option for treating patients, supported by well-conducted, randomized phase 3 trials. We also know that the addition of nivolumab to chemotherapy showed the same strong signal in terms of progression-free and overall survival. That was a smaller study, so it wasn’t a definitive randomized phase 3 trial. Lastly, the addition of pembrolizumab to chemotherapy also outperformed chemotherapy alone, with significant improvement in terms of progression-free survival; there was a strong trend that did not meet statistical threshold in terms of overall survival. We have these—not just 1 study, but 4 studies—all pointing in the same direction and telling us that this is the right strategy to adopt when we treat our patients.

The only reason why I would not use a checkpoint inhibitor along with chemotherapy for somebody with a diagnosis of extensive-stage disease is because they cannot get chemotherapy. If they have problems that would make chemotherapy prohibitively toxic, that would be the only reason why I would not give them the immune checkpoint blockade along with it.

That brings up the other question: What is the role of immunotherapy itself when we compare how we use it in small cell to non–small cell lung cancer? We all recognize that we have different ways of using checkpoint blockade when it comes to non–small cell lung cancer. We can use it alone if you have evidence of PD-L1 expression, whether low or high and depending on patient status. You can use it in combination with chemotherapy for the entire duration of the induction phase, or we can use this combination immunotherapy by itself. With more recent data, you can even do abbreviated chemotherapy along with immunotherapy and then continue with immunotherapy.

For small cell lung cancer in the front-line setting, we have only 1 option of doing this, and that is in combination with chemotherapy. My own impression of why we have stuck with this goes back to what I said earlier, which is that for a large proportion of patients with small cell lung cancer, when you look at the tumor samples under the microscope, they are very cold immunologically. Relying on immunotherapy alone will require us to understand the biology of small cell [lung cancer] better and be able to identify the small proportion of patients where you could make a case for testing immunotherapy by itself, but I don’t think we’re anywhere near there right now.

Advances in Extensive-Stage Small Cell Lung Cancer

 Let’s shift gears and move into the recent advances for small cell lung cancer. Immuno-oncology [I/O] has rapidly changed over the past 5 years and changed how we treat many tumors. What’s the rationale for using immunotherapy in small cell lung cancer?

 Small cell lung cancer has certain unique biologic properties, some of which make us feel that they should respond to immunotherapy and other sides that make us feel that immunotherapy will probably not be successful based on our current understanding of how some patients or tumor types will respond to immunotherapy by itself. We know that patients with tumors that have very high tumor mutational burden in general tend to respond better than those with low tumor mutational burden. With small cell being one of those tumor types with high tumor mutational burden, one would expect that this is a tumor that would be vulnerable to checkpoint blockade, so-called immunotherapy.

The other aspect of small cell, the way you look at it is actually under the microscope when the pathologist looks for immune cells. The majority of these tumors do exclude immune cells, so they tend to be immunologically cold. Even though the phenotype of the tumor should suggest vulnerability to immunotherapy, the absence of tumor infiltrates and lymphocytes in a large proportion of these patients speaks to the other side of why immunotherapy might not work. That is not unique to small cell; it’s what we struggle with with all tumor types. The goal is to figure out those patients who are likely to benefit and use this immunotherapy for them as best we can. For those who are less likely to benefit, we need to come up with other strategies that will make it possible for immunotherapy to impact the outcome.

The approach that we have now as established standard in the front line is perhaps allowing us to take advantage of both of these phenotypic characteristics. By adding immunotherapy to chemotherapy, we are potentially turning the cold tumor into a hot one, and by inducing tumor-associated antigen with the use of chemotherapy, that could serve as an attractive target for the immune cells to be able to get into the tumor microenvironment. Why this is all over the place is because we don’t have dedicated study just in small cell. We borrow knowledge from everywhere, and with the little we know about small cell biology, there is rationale for the treatment to work, but there’s also rationale for it not to work. It’s a matter of figuring out within that entire mix what subset of patients will benefit and what we do for those who are less likely to benefit to make them responsive.

 All 3 of us have been involved in lung cancer care and clinical trials for a while, so we’ve seen a lot of failed trials in extensive-stage small cell lung cancer, including a couple reported recently. Could you provide some perspective on those trials and talk about why these combination chemotherapy/immunotherapy trials have been different and why we’ve seen the progress with these combinations?

I was talking with colleagues who are more seasoned than me, and they were telling me that they haven’t seen some positive news in small cell lung cancer for the last 38 years. What we’re seeing with the addition of immunotherapy to standard chemotherapy is totally raising the standards for our patients. One of the reasons is that we do not have a very good understanding of the biology of small cell lung cancer. If you think about that, this is one of the diseases where we don’t have a very good handle on things. We don’t have a lot of good measures to understand how the medications work, and it all comes with the clinical complications of that because when the patients come so quickly and we have to treat them, we might never be getting enough mileage. When they progress, they progress so fast that we don’t have all this important tissue that will generate the clinical data that would help us have better science. Now, the fact that we have seen that immunotherapy has very good activity in small cell lung cancer in the context of the combination has to validate what we are sharing with our patients.

 I agree. It was so exciting with the chemotherapy-I/O trials to finally see an overall survival benefit in small cell lung cancer because, as you said, it’s been 30 years. Finally getting over that hump and showing that we’re actually helping people live longer was so great to see.

Rationale for I/O therapy in Extensive-Stage Small Cell Lung Cancer

: You’ve both touched already on how aggressive this is, so talk about how that factors into your initial work-up and treatment. Historically, how has this patient population been treated? What were their treatment options in the past?

: We know that small cell lung cancer is aggressive and fast growing, and for that reason, we always want to get the patient on treatment as soon as possible. Whether it is limited stage or extensive stage, there’s really not enough time to waste in working the patient up. This has been the bane of the field, that we tend to establish diagnosis based on whatever sample we can get, whether a cytology sample or fine needle aspiration biopsies, and that we don’t end up with a significant amount of tissue. This is not a time where we go back and say we want to get genomic information or any of that form of pathologic authorization. Just a basic diagnosis of small cell has been sufficient for us to move forward with treatment.

Going back in time, small cell used to be looked at as a very poor prognostic situation for patients, where a lot of patients didn’t get any treatment at all. We looked at the SEER [Surveillance, Epidemiology, and End Results program] database recently, going back about 3 decades, and we still see that, even in the United States, close to 30% to 40% of patients don’t get treatment for their diagnosis of small cell—in part because of the historical experience of nothing worked, so why put a patient through something that’s not going to help them? I think if we look back to today, which has been influenced by the last 2 decades with the use of platinum-based doublet chemotherapy, we know that this approach has had meaningful impact on patients’ quality of life in terms of reducing symptoms. For patients who do respond—about 50% to 60% of patients will respond to platinum-based doublet chemotherapy— it does have an impact on survival as well.

We’ve all come to accept platinum-based doublet chemotherapy as the platform on which we build whatever strategy we want to treat the patient. For those with limited stage, the addition of radiation and chemotherapy together using platinum doublet has been shown to be safe, and that resulted in a better outcome than radiation alone or chemotherapy alone. More recently, the addition of immunotherapy to that platform is helping to advance and improve the outcome for patients with extensive-stage disease.

In terms of reviewing treatment options with patients and the urgency of getting on with the treatment, I think we have to let them know we have very limited options, but what we have is most likely going to work for the majority of the patients to start with. In the frontline setting, 60% to 70% of patients will respond to the treatment. Where we are failing is when the disease stops responding and relapses. We do not have very effective salvage therapy, and that is what eventually, unfortunately, leads to the demise of the patient.

In setting the goals, it’s usually a matter of being very open and candid with the patients, that if we don’t do anything, we know what’s going to happen. The median survival for untreated patients is only about 3 to 4 months, and that has not changed over the last 3 decades. That’s why there’s been an improvement in supportive care; if we don’t treat small cell at all, patients don’t live much longer from the time of diagnosis. If you do treat, that is where the discussion comes for the patient in terms of what is important to them. These are well-established treatment options; we know their adverse effect profile, and we know how to manage them, whether with dose reduction or growth factor support. Once we’ve told the patient what to expect, then it becomes a matter of them balancing that against what their own expectations are. A lot of patients, when they come in, they’ve already heard so much about small cell that they come in with the idea that there’s really nothing you can do to help them. It’s more a matter of helping them see the potential benefit of going on with the treatment.

I think that when compared to non–small cell lung cancer, especially where we’re talking of the early stages of the disease, we tend to talk more about a cure. When the patient goes to surgery, they get adjuvant treatment, even for locally advanced where they get chemoradiation and then get consolidation with immunotherapy, where we put cure front and center. Unfortunately, that has not been the case with small cell lung cancer, especially the extensive-stage disease. The reason for that is even when a patient responds, we know that the relapse rate is very high—almost 80%—and when that happens, the outcome is not as great. You have to situate that reality against the goals for the patient, and that is where you have a joint discussion to ask what is most important: Quality of life, quantity of life, or both? Then, we try to marry those 2 to craft the most tolerable intervention that we can offer the patient to help improve the outcome.

 What advice do you have for our community physician colleagues when they’re facing a patient recently diagnosed with extensive-stage small cell?

 I think that Taofeek explained very well why it is so urgent to treat the patient. First, we have to make sure that all physicians believe that the treatment is important in small cell because we have such good outcomes. It’s very sad when we hear about cases of someone who was diagnosed, and because of the description of the bad prognosis, they didn’t do anything. The second thing: We see in our practice that even very sick patients, while symptomatic, may respond; this number that Taofeek discussed, 60% to 80%, can get better. In oncology, we have this paradigm of not treating patients with bad performance status. I can tell you that with small cell lung cancer, we may all feel a little more bold to treat patients who are symptomatic due to their disease, even though they have small cell lung cancer, because we know that the response rate is very good.

I don’t know why the symptomatic small cell lung cancer, in my experience, is usually the Friday afternoon patient. It’s always that the urgent thing will happen on Friday afternoon, especially before a long weekend, but this is a case in which we do not wait for treatment. We admit the patient and institute the treatment appropriately because it is urgent. As we discussed before, the doubling time of this disease is very strong, so in cases with liver disease, you may see liver function enzymes rising so high that if you leave treatment for Monday or for the next week, you would not have an appropriately healthy liver to treat. I have seen a couple of cases, and my previous experience is that my patients became so thrombocytopenic while waiting for treatment, which caused a big battle for them. For us, we teach our fellows that this is an oncologic emergency and that we should start treatment right away. The 2 things we know are that treatment improves survival and symptoms, since we are talking about targeted treatment here, and how urgent it is.

Aggressive Nature of Extensive-Stage Small Cell Lung Cancer

In your clinical practice, how do the small cell and the non–small cell patients differentiate? What are the differences in staging and prognosis between small cell and non–small cell? Konstans, I’ll let you take this one.

 In general, the patients with small cell, especially once they become symptomatic, they’re quite sick, and we will be discussing more about that. When it comes to staging, we always advise to have a full-body staging, including a CT [computerized tomography] of the chest, abdomen, and pelvis, or a PET [positron emission tomography] scan done in comparison with an MRI of the head because we know how common it is for small cell to cause brain metastases. Even though we like TNM the tumor, node, metastasis staging system and it is important for registration reasons, it is important to differentiate between limited and extensive stage. This is more practical, it has been validated in many clinical cohorts, and we differentiate the staging between non–small cell and small cell because small cell will use limited versus extensive staging.

We can discuss what is limited and extensive. We define limited stage as the disease that is in the ipsilateral hemithorax and in lymph nodes that could be safely encompassed into radiation; also, we can do the radiation and chemotherapy that Taofeek discussed. Do we still find any value in the TNM? I would say yes, mainly in the very early small cell lung cancers, the ones that would be T1, T2. We might have potential room for surgery still, and these are the patients who do better than anybody. I would say yes, let’s keep the TNM, but for our clinical practice, the distinction between limited and extensive stage is the most important.

 When you’re seeing a patient in the clinic, what do you quote for expected prognosis in limited-stage versus extensive-stage small cell?

 When it comes to limited stage, not a lot of things have changed. For limited stage, we have an overall survival of 17 months, with a 5-year survival of 20%. The survival curves totally change depending on the stage. We have much better prognosis for patients who are diagnosed early, usually through screening or for another reason. These patients can do very well with surgery and always adjuvant chemotherapy. For limited stage, not a lot of things have happened, since immunotherapy has changed things mainly in the extensive stage. This is where we will be quoting the new survival rates that we’ll be talking about.

Differentiating Small Cell Lung Cancer and Non-Small Cell Lung Cancer

 presentation, broadcasting virtually from across the country. My name is Kathryn Gold, I’m a physician in medical oncology, specializing in thoracic and head and neck cancers here at UCSD [University of California, San Diego] Morris Cancer Center. Today’s discussion will be focused on immuno-oncology [I/O] in combination with chemotherapy for the first-line treatment of extensive-stage small cell lung cancer. Joining me today in this discussion are my colleagues, Dr Konstantinos Leventakos from the Mayo Clinic in Rochester, Minnesota, and Dr Taofeek Owonikoko from Winship Cancer Institute at Emory University in Atlanta, Georgia.

During the next 60 minutes, we’re going to navigate through the new role of I/O therapy in combination with chemotherapy for first-line treatment of extensive-stage small cell lung cancer and the questions surrounding how to use this approach in clinical practice. Let’s dive in and get started with our first topic.

First, we’ll be covering some of the characteristics of small cell lung cancer and how it differs from non–small cell lung cancer. Could you two discuss a little bit about how often you encounter patients with small cell lung cancer in your practice, and how do these patients typically present? Taofeek, I’ll let you take the lead on this one.

 Thanks for joining us from across the country. As we know, lung cancer is the most common cancer type that we deal with in the United States; worldwide, it’s still a major disease burden. The majority of our patients will have the non–small cell category, but small cell is not to be underestimated. About 13% to 15% of our patients with lung cancer will have the small cell variety, and if you think about the diagnosis of about 240,000 a year in the United States, that’s somewhere on the order of 30,000 to 40,000 patients with small cell lung cancer. These are not rare cases; we all have them in our practices, depending on where we’re located in the country. I practice in the Southern Belt—what we call the Tobacco Belt—where a lot of our patients will have much more advanced stages of lung cancer in general, but the proportion of patients with small cell may be higher than what you’d see on the West Coast, or maybe even in the Midwest to some degree.

For my thoracic-focused practice, I would say about 20% of it is patients with small cell lung cancer. Of this 20%, the majority of patients are coming in from outside facilities following their frontline treatment for either salvage therapy or participation in clinical trials. In terms of the distribution by stage, I think this cuts across everywhere we practice. The majority of our patients present very late. I don’t think it’s necessarily because of ignoring the symptoms. I think it’s because small cell, as we know, has a very rapid growth rate; the biology is very aggressive. By the time the patient is diagnosed, they’re already beyond the stage where we can start talking about cure. Unfortunately, 60% to 70% of our patients are incurable when they present with extensive-stage disease. One-third of them will present with limited-stage disease, and when we are lucky at that stage, we can at least shoot for a cure, which we know is not achievable for every patient. With the combination of chemotherapy and radiation that we use, we can anticipate about one-fourth of patients with limited stage will achieve durable control of disease, which may eventually turn into a cure.

 Konstans, how do you see people presenting to your clinic with small cell?

 This is a very common situation, as Taofeek said, because lung cancer is the most commonly seen cancer in the United States; 15% of patients with lung cancer who have small cell is still a good amount of patients. Most of the patients present with symptoms that would either be generalized, where the primary care doctor gave the CT scan and found a mass that was biopsied and discovered to be small cell lung cancer, or any findings, including patients who were identified to have small cell through screening. This is new, that we might be seeing a little more early-stage small cell lung cancer because of screening. I agree with Taofeek; with the modalities that we are using, this is the time that we may be talking about a cure. In our center, we have a big population. We are a primary cancer center, so we see first diagnoses of small cell; we also have a lot of second opinions for patients who have already had first-line treatment.

 What are some of the risk factors that you observe in your patient population for small cell?

 I think that we all agree that the main risk factor is smoking, and the risk of small cell lung cancer increases with the amount of smoking that someone has done all their lives. We see it also in ex-smokers, even though we always advise to quit smoking. It is important to say that with the policies to restrict smoking, we have seen the numbers of small cell coming down. We have seen more of an increase in women rather than in men, and that probably shows all the physiology of smoking and smoking-related cancers.

Konstantinos Leventakos, MD, PhD Mayo Clinic

Articles