 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.

Videos

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

Advances in Extensive-Stage Small Cell Lung Cancer

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

Aggressive Nature of Extensive-Stage Small Cell Lung Cancer

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

Background of Small Cell Lung Cancer