With that, I thought I'll bring a case to all of you. And we could talk about how each of us would think about managing this a little bit differently. This is a patient that I took care of. This is a 68-year-old male. Former smoker had an extensive smoking history of about 60 pack years. Had CAD hypertension, atrial fibrillation, routine meds to manage all these Astatin, Metoprolol, aspirin, presented with shortness of breath. And imaging revealed a large left pleural effusion, worsening pericardial effusion, and there was a question there may be possible early tamponade. Thoracentesis was performed. Flux placement was initiated and pathology from the plural fluid analysis revealed small-cell carcinoma. We went on and we performed further imaging. We found plural hepatic and brain m metastases that were confirmed both on pet scan, as well as an MRI. His performance status was great fully capable of doing all activities and shortness of breath had improved largely with the placement of the Flux catheter. We initiated therapy with carboplatin etoposide and durvalumab based on the Caspian study. And as you can see here, radiographic response was pretty brisk. There was a significant improvement in plural effusion. You see the baseline scans on the far left. We have post cycle 2 scans in the middle and then post cycle four scans. The pleural effusion, as well as the pericardial effusion improved, but also the significant reduction in disease burden or metastatic disease burden, I should say, which shrinkage of hepatic metastatic disease. And you can see very clear improvement and he continued to feel better, was breathing better, really had minimal toxicity from his symptoms. I'll tell you why I chose this regimen and then I'll open it to ask all of you. I thought that it was very important for me to come in with chemo immunotherapy. This is a patient who came to me in the outpatient setting. I could initiate treatment pretty quickly. We'll talk a little bit more about how we choose between the different PD-L1 inhibitors, but based on what we've seen, I thought it would be perfect to initiate concomitant, chemotherapy and immunotherapy. And I went with it, and it worked. And after that, he was on durvalumab maintenance for a while. Maybe I'll start with you, Vivek, how would you approach such a patient and tell me your management thinking?

: I would completely agree with what, what with the management of this patient, because here you have a patient who is, has pericardial effusion, who's progressing quickly. And as Taofeek mentioned earlier without starting anything, we would've lost this patient. And we know that cisplatin etoposide is our active agents used for the last 30 years. They do respond quickly and briskly, and you want to combine all the active agents for this disease. The management was appropriate. Absolutely completely agree.

One teaching point here is the brain, right? The patient had brain metastases at baseline. And because this is such a chemotherapy sensitive disease, many of us clinically would start with systemic therapy, not radiate the brain first and wait for chemo. And, many of the trials in small cell required treatment of brain metastases before enrollment on First line trials and that that's changed now with the recognition that systemic therapy can be effective in the brain and can actually, for patients who are PS zero, who are asymptomatic from a neurologic perspective you can start with systemic therapy and follow closely.

: You raise a very good point. Do you usually sandwich whole brain radiation or radiation to the brain, I would say, in between cycles, or do you wait for the first four cycles? Tell us your preferred approach.

If the patient's doing well, we'll continue to follow and watch. And if a patient has brain metastases, a diagnosis, we will monitor those as we would the rest of the body for response. If those are non-responsive and they can be somewhat less responsive than the rest of the body, then we would intervene earlier with radiation. But otherwise, I would complete the full course of chemotherapy.

And then maybe at post cycle 4. How often I guess how often would you then continue to perform brain imaging after that? Let's say post cycle four, you came in, you had a very good response. How often do you continue brain imaging? And then I'll ask another follow up question after that.

I'm nervous if we have untreated brain metastases off chemotherapy. Andif we completed the 4 cycles of chemotherapy, the patient had a nice response in the brain. I'm worried that they're going to progress. I would think about radiation at that point. They're off chemotherapy, they're going on with their immunotherapy maintenance. I would consider doing it at that point. If you do not radiate at that point, you need to monitor pretty closely, like every couple of months to check for brain metastases and be on the outlook for new neurologic symptoms.

Right. Taofeek question for you, do you do 4 cycles or 6 cycles of chemotherapy, immunotherapy? What's your preferred approach?

: Generally, for majority of the patients whether with, or without immunotherapy, I tend to just go for 4 cycles of platin double chemotherapy. And that is based on the fact that we never had any head-to-head prospective trial to look at 4 versus 6, but small data that we have in small cell and much more extensive data and non-small cell. We know that beyond 4 cycles, we don't get a lot of benefit. It's more toxicity, but having said, I want to take a step back to some of the questions you asked before and bring that back to the add addition of immunotherapy to chemotherapy. We all agree. That's it's a step forward, whether it's incremental or transformational, we can all argue about that, but for the patient that we take care of the way we also assess the level of improvement that we've witnessed, is important than when we look at it and say, well, it was only like 2 1/2 month improvement in media and overall survival. We actually do ourselves a great disservice in terms of where the field has been and where we are now. I tend to look at this more as what is the magnitude of benefit as opposed to measuring the month, but more appropriately in terms of the hazard ratio, which is difficult to discover with a patient at least in an academic setting, like this is important that we bring that out, that adding immunotherapy to chemotherapy reduce the risk of a patient dying of the disease by almost 30%. Now, for non-small cell, if we say that a lot of drugs got approved based on that magnitude of improvement and even less than two months improvement going back 15, 20 years ago, small cell suffers from the small bladder syndrome because it's in the chest with non-small cell and we've made so much advances with non-small cell that immediately, we now expect small cell to perform at the level that non-small cell is performing. Whereas it took us 20 years to get there. Which brings to point this case that you really used to illustrate what we do for our patient. A patient with non-small cell lung cancer, presenting like this, where we got fully to make the diagnosis, I think majority of us will take time to get additional tissue, to understand the biology of the disease better, and then come up with the more appropriate treatment, but over the past 3 decades, we've been satisfied with this approach of just make a diagnosis and then let me move forward because our initial treatment is going to work well just like it did here. The problem is always, when it stops working, then we don't know what to do. What is different? Why did that patient respond? With the effort in the field now we are very hopeful that we're going to find one single target, that's going to force all of us to have in a patient like this, to do a proper biopsy so that we can better understand the biology of the disease.

Videos

Charu Aggarwal, MD, MPH, presents the profile of a patient with small cell lung cancer with brain metastases to spark a discussion on treatment approaches in the frontline setting.

Patient Profile 1: A 68-Year-Old Male with SCLC and Brain Metastases

Treatment of small cell lung cancer has changed significantly. I'm going to ask each one of you. What do you think is the most significant progress or change that we've made in the field? I'll start with you, Jared.

There's one biggest change. I'm glad to go first. If we look back on the last decade, the biggest advance is the addition of PD-L1 inhibitory therapy being added to the standard platinum etoposide regimen. If you look at the evolution of front line therapy before that, it wasbased on toxicity, advantages and convenience advantages these matter. But PD-L1 is our first survival advantage in a long time.

: I would entirely agree with that PD-L1 inhibitors unfortunately do not work in most patients. But when they do work, they can be transformative. That is, there are patients who have durable responses even in extensive stage disease. These can really change a person's fate. And that's something that was a long time coming and has clearly redefined our standard of care.

I would agree with that. The other way to look at this in terms of what has changed is what is it that we were doing before that we stopped doing? If we all look at our practice pattern these days the use of anthracycline based chemotherapy probably now dropped off significantly, especially in the US [United States] and I would say maybe in Western Europe, except for some, maybe some die hard believers in anthracycline chemotherapy. Most of us do not use those agents. We all know how toxic regimen could be for a patient who is already frail. The other thing that has changed is, or that's potentially coming back is as people continue to use screening studies to find patient early. Now we know that patient with stage one disease. We are also now open to maybe offering them the surgical approach, which before none of us would even entertain. Those are some of the new re-evolution. To say of old strategies that we are now open to entertaining going forward.

: I completely agree with Jared, Charlie, and Taofeek. The game changer has been the addition of immunotherapy to the frontline therapy. Jared said a decade, but I would disagree for the last 2 to 3 decades we didn't have any changes. Change with that addition of immunotherapy. That's a dramatic change, although that the, the overall survival difference is minimal. It's an incremental, benefit to patients and some patients towards the tail end of the curve who do benefit from immunotherapy benefit for a long, long period of time.

: I will just add that, yes. I agree that addition of PD-1 and PD-L1 inhibitors has been great, but I think for the first time we also have new second line therapies. We are moving away from using our old standards of recycling a taxane or trying to avoid Topotecan as best as we can, as much as we can. And we have drugs like Lurbinectedin, and there's a lot of excitement about bringing in maybe small molecules. And this is the kind of excitement we haven't seen in small cell in a while. At ASCO [American Society of Clinical Oncology] and other annual meetings, we are seeing that the small cell sessions keep getting bigger and bigger. This is all going in the right direction.

The panel discusses how the field of small cell lung cancer treatment has changed in recent years.

Progress in the Treatment and Management of SCLC

Charlie, how do you use or what staging system do you use for current management of your patients. Could you talk to us about different staging systems and what's your preferred?

: The International Association for the Study of Lung Cancer has put out a statement, and firmly believes, that we should stage small cell lung cancer as we do every other lung cancer that is using the TNM [tumor, nodes, metastastes] staging system. And in fact, those stages are prognostic for small cell lung cancer. From a practical perspective. Most of us favor just separating small cell into what we call limited stage and extensive stage disease. That's a very practical definition, and one that dictates the approach to therapy. Limited stage disease is disease that's combined to one side of the chest one hemithorax, and that can be generally encompassed within a radiation port that the radiation oncologist feels that they can adequately treat effectively to get good local control. For those patients who have limited stage disease, the standard of care would be a combination of radiation and chemotherapy with the radiation really for local control - chemotherapy really has 2 functions there. One to synergize with the radiation - it's a radio enhancer makes the radiation more effective, and probably more importantly actually gives systemic control treating the rest of the body for microscopic disease, which is probably present in almost all patients who have a diagnosis of limited stage small cell lung cancer. Extensive stage is just the opposite, that is, it's anybody who does not have limited stage disease whose disease has progressed to the point where they no longer can be effectively encompassed within a radiation port. Frequent sites of metastasis would be the contralateral lung. Brain is very common in small cell lung cancer patients, bone liver, and adrenal.

And you outlined the differences between limited stage and extensive stage. We tend to use these in practice also more frequently because they have such clear-cut sort of categories in terms of what treatments we recommend, but also prognostic categories. We know that extensive stage - patients with extensive stage small cell lung cancer, we can adequately define what their overall survival would be, what kind of clinical trials they would go fall into. Vivek I would like to ask you, are there any current biomarkers that you're using or interested in for patients with small cell lung cancer?

: Absolutely. Thank you so much for the great question. As Jared said, under the light microscope, they all look as small round blue cell tumors and they do specific stains to showcase and also confirm that it is small cell lung cancer. And in the next in sequencing era we have extensively studied in many academic centers the biology of small cell lung cancer inactivation of RB1 and TP53 gene coded by the retinoblastoma gene and the P53 is, are near a ubiquitous events in small cell lung cancer. Now beyond this 4 different molecular classifications or subtypes have been described again, they are of academic interest, mainly the SCLC type A small cell lung cancer type N type P and Y based on the expression of transcription factors. Also, we see mic amplification and also not mutations, but again, these are to date of academic interest for us. And they don't guide us clinically in terms of how we treat patients that present to us in our clinic. So the short answer is we are working on it and no.

They give us hope though, that we're starting to understand the biology and subtype. And there's a shared optimism amongst many in the field that they're a hint of what's to come, even if, if not ready for clinical practice yet.

Charles Rudin, MD, PhD, explains the prognostic staging systems used for small cell lung cancer.

Use of the TNM Staging System in SCLC

® Peer Exchange titled "The Evolving Treatment Landscape of Small Cell Lung Cancer." I'm Charu Aggarwal. I'm a medical oncologist at the University of Pennsylvania's Perelman School of Medicine and the Abramson Cancer Center, [Philadelphia, Pennsylvania]. I'm joined today by a panel of experts in the field of small cell lung cancer, and I would like to welcome them, and they will take an opportunity to introduce themselves. Dr Taofeek Owonikoko.

: Hello. I'm pleased to be part of this panel. I'm a professor of medicine at University of Pittsburgh UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania.

: Hi. I'm Charlie Rudin. I'm the Chief of Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York.

: Hi, I'm Vivek Subbiah from the University of Texas MD Anderson Cancer Center. I'm a medical oncologist and an associate professor in Houston, Texas. Thank you.

I'm Jared Weiss. I'm a professor of medicine at UNC's Linebarger Comprehensive Cancer Center and Section Chief of thoracic and head and neck oncology.

Welcome everyone and thank you for joining me today. Let's get started on our first topic today. We are going to talk about small cell lung cancer, recent excitements, lot of data being presented. I wanted to just open with incidents of small cell lung cancer. We know that incidents of small cell lung cancer has been declining. It's about 13% or 15% of all newly diagnosed patients with lung cancer. And most of these unfortunately present with extensive stage disease. Most often with brain metastases, and most often patients present an extremist. We sometimes have to initiate therapy in the inpatient setting necessitating us to come in with chemotherapy, maybe not a combination chemotherapy immunotherapy approaches. Dr Weiss, can you describe to us how patients usually present to you? Can you talk about are there specific signs and symptoms and how do you work up a patient with a diagnosis of small cell lung cancer?

The first thing to say is that small cell lung cancer is almost exclusively a disease of patients with a heavy smoking history. And they come to the disease with the comorbidities associated with smoking, as well as the socio-economic disadvantages and the stigmatization that come with that. Physically, the presentation is very often in the central chest. A lot of central chest presentation, central lymph node presentation. This can clip off the central vessels in the chest. This can clip off central airways. And as a consequence, small cell presentation is often dramatic. It's often a highly symptomatic patient. The solid tumor we see most often in the emergency room. As you referenced, often patients are admitted. Fortunately, the disease is very chemotherapy sensitive, and we can help these people pretty rapidly with administration of that first cycle. Small cell also likes to metastasize. It's very aggressively metastatic disease, as you mentioned very brain trophic, which can cause a lot of suffering. For our workup, it's important to get cross-sectional imaging, at least down to the adrenal glands in the US, [United States] we're usually covering the entirety of the abdomen. And often we're getting a pet scan which de facto gets a wider area and very, very important to have an MRI of the brain with contrast. At that point, like any other solid tumor, you want a biopsy the most advanced appearing site, and if you have a potentially limited stage patient, that's usually endobronchial ultrasound guided biopsy of a lymph node. And in the case of an extensive stage, the most easily accessed remote site. Under the microscope, it's usually not a terribly hard diagnosis. It's a small round blue cell tumor, although you do sometimes see an extraordinary amount of immunohistochemistry done to confirm what should be somewhat straightforward.

Taofeek, I was wondering if you could talk to us about the importance of establishing the diagnosis early, starting treatment how do you go about doing that and tell us what we should all be doing?

It is important for this disease that we - thank you for that question - It's important for this disease that we find the patient early and that we initiate treatment as soon as possible for two main reasons. One is majority of our patient when we find them after they've presented with symptoms, it's usually then at the incurable extensive stage of the disease. And the second is a disease that's associated with a lot of symptoms. When you allow to go too far, it may get to the point where you are not even able to offer the patient some of the effective treatment options that we have. Having said that we currently do not have any reliable way to detect this disease in patient before they present with symptoms. If you all remember the data from the National Lung Screening Trial, which was looking for any type of lung cancer, it's disappointing that that trial also was able to catch patient with small cell lung cancer, but majority of them was already at the advanced stage setting. And therefore, there was no survival impact for that small cohort of patient with small cell. Having said that when we have a patient with a lot of symptoms, we want to make sure that we establish diagnosis. And I think that's a double-edged sword that has gotten us to a situation where we are comfortable dealing with small amount of tissue sample to establish the diagnosis without actually going through the whole process of trying to define exactly what is going on with the patient, because we want to initiate treatment as soon as possible. The other thing that is somewhat disappointed, which is important for us to detect and start treatment early is, when you look at the US population of patient diagnosed with small cell lung cancer, 40% of them may not get any treatment at all. And that reflects the belief by most of our non-oncology colleague in other specialties like pulmonary and internal medicine, believing that once you have a diagnosis of small cell, that there's no effective treatment, I shouldn't even bother going through any treatment. So that is something that maybe over time with education with our peers and colleagues, we are going to be able to change that paradigm.

That's a challenge. And we definitely see that in many of our situations with newly diagnosed patients.

Drs Owonikoko and Weiss provide a brief overview of small cell lung cancer and the vital importance of an early diagnosis to improve patient outcomes.

Overview of SCLC and Importance of Early Diagnosis

Vivek Subbiah, MD, an associate professor in the Investigational Cancer Therapeutics Department, and Center Clinical Medical Director of the Clinical Center for Targeted Therapy of the Cancer Medicine Division, at The University of Texas MD Anderson Cancer Center, discusses outcomes with selpercatinib (Retevmo) in patients with 

Selpercatinib achieved an objective response rate of 47% per investigator assessment, according to Subbiah. Responses were observed across a broad spectrum of cancers with 

 fusion positivity, including pancreatic cancer, breast cancer, salivary cancer, sarcomas, carcinoid cancer, rectal neuroendocrine tumors, small intestine tumors, xanthogranuloma, ovarian cancer, and pulmonary carcinosarcoma, Subbiah explains. 

Notably, only patients who had measurable disease were included in the waterfall plot presented during the 

, Subbiah says. Certain patients, including 1 patient with xanthogranuloma who experienced a complete response, were not included in the presented results, as they had non-target lesions or did not have a post-baseline target lesion measurement, Subbiah explains.

Selpercatinib demonstrated activity across all tumor types that harbored a 

 fusion, and yielded promising tumor response rates, Subbiah concludes.

Vivek Subbiah, MD, discusses outcomes with selpercatinib in patients with RET fusion–positive cancer.

Vivek Subbiah, MD

Articles

Patient Profile 1: A 68-Year-Old Male with SCLC and Brain Metastases

Progress in the Treatment and Management of SCLC

Use of the TNM Staging System in SCLC

Overview of SCLC and Importance of Early Diagnosis

Dr. Subbiah on the Efficacy of Selpercatinib in RET Fusion–Positive Cancers