What do you think is the role of immunotherapy in the first-line setting? Is that used most in extensive or mostly use of limited-stage disease?

We can say that extensive-stage small cell lung cancer patient immunotherapy is a standard combination with chemotherapy platinum receptor. We have the data from the CASPIAN trial ((NCT03043872), and from the IMPOWER133 trial (NCT02763579). For patients with limited-stage small cell lung cancer, IO is not a standard because the STIMULI trial (NCT02046733) assessed the role of maintenance therapy after chemoradiotherapy in patients with limited-stage small cell lung cancer. The IO tested in this trial was a combination of [nivolumab ipilimumab] and this randomized phase 2 trial was negative. Today, there are a number of ongoing trials assessing the addition of immunotherapy to the standard radiochemotherapy. The results of these trials are still pending. So, for limited-stage small cell lung cancer, IO is not a standard at least today.

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A brief review of the role that immunotherapy agents play in the frontline management of patients with small cell lung cancer.

Small Cell Lung Cancer: What is the Role of IO Therapy in the Frontline Setting?

So, what are the treatment options today for patients with extensive-stage small cell lung cancer? We can say that for decades platinum-based chemotherapy has been the preferred first-line treatment for these patients. We know that the results of this treatment are not fantastic. But these results are better than the best supportive care, but we know that median overall survival is around 9 to 10 months for these patients. In terms of platinum agents, we know from meta-analysis on individual patient data that there is no difference in terms of overall survival between cisplatin and carboplatin. There are differences in terms of toxicity profile with cisplatin being more toxic with nausea, vomiting, and renal toxicity, while carboplatin is more toxic in hematology. Therefore, in extensive-stage cell lung cancer, cisplatin is often substituted by carboplatin. That's the first point.

After the first-line chemotherapy, several trials tested the maintenance treatment with different drugs. None of these trials showed improved outcomes compared with the standard 4 to 6 cycles of platinum based chemotherapy. So, maintenance treatment with a chemotherapy agent doesn't add anything. Recently, immunotherapy with anti-PD-L1 agents are really modified as a treatment landscape for small cell lung cancer. There were 2 positive randomized phase three trials who are very well known today. First, the IMPOWER133 trial (NCT02763579) assessed the addition of atezolizumab to standard chemotherapy with carboplatin plus etoposide in patients with extensive-stage small cell lung cancer. These patients benefited from the addition of atezolizumab in terms of PFS [progression-free survival] and in terms of OS [overall survival]. It was 2 months again in OS, the median overall survival moved from 10 appointments to 12 appointments. It's statistically significant, but it's also clinically meaningful. The second randomized phase 3 trial, which is well known as a CASPIAN trial (NCT03043872), design was not exactly the same. It was a 3-arm randomized trial with the first standard arm with platinum etoposide, the platinum was cisplatin or carboplatin.

There were 2 experimental arms in this trial. The combination of durvalumab plus chemotherapy or the combination of durvalumab, serplulimab plus chemotherapy, so anti-PD-L1, anti-PD-L4 plus the 2 drugs of chemotherapy. This trial is positive for the addition of durvalumab to chemotherapy with very comparable outcomes compared with IMPOWER133. Other important information is that the addition of serplulimab to durvalumab chemotherapy doesn't translate into improved outcomes. Today, we can say that eligible patients to immunotherapies, as a standard of care today, is a combination of chemo plus and anti-PD-L1 agent is atezolizumab or durvalumab.

Moving on to discuss the treatment armamentarium in small cell lung cancer, expert oncologists consider current standards for frontline therapy.

Overview of Frontline Treatment Options in Small Cell Lung Cancer 

 I think, overall, the combination of adverse events is not too much of a problem. I think that’s what we have seen. It’s more the context, what we have to think about and what’s coming as our next topic now, is just how we proceed from here. If not all patients benefit, it doesn’t make any sense to increase toxicity by using the same kind of chemotherapy or IO [immunotherapy] combination. What do you think, what would be the next step to develop a better outcome in these patients with small cell lung cancer? Still a median overall survival of 12.9 months. That’s still not very good. There’s still a lot of room there to improve outcomes. What would you think would be the next step, how we can just add something to that portfolio, to make the overall outcome of our patients better?

As always, there is a temptation to add a force agent. As we discussed previously, is the addition of tremelimumab, for example. There is also data with ipilimumab. So anti-CTLA-4 inhibitors don’t really add to small cell lung cancer. In terms of immunotherapy, there was also data with anti-TIGIT antibody, but the results are disappointing. I’m not sure that this kind of agent will be helpful for small cell lung cancer patients. There are additional new agents who are currently in development. In terms of chemotherapy, antibody-drug conjugates, and bispecific antibodies. My hope will be directed more on these new drugs than the classical checkpoint inhibitors.

 You’re already talking about personalized medicine for small cell lung cancer patients. I think this is the future if you have the right biomarkers. You have mentioned that TIGIT didn’t work. I think this is another example [where they] didn’t preselect the patients, so things failed. We have an ongoing trial in Europe or globally, called IMforte [NCT05091567], which is a trial where you have the standard of care 4 cycles, platinum-based chemotherapy, etoposide, and atezolizumab. Then you have a maintenance phase where you add lurbinectedin. There are other trials currently enrolling using other options like PARP inhibitors, or other things, to improve outcome in this cohort. It does make sense that you preselect your patients by clinical means. Once you have made it through 4 cycles, maybe you’re good for maintenance therapy and then you can add something. The patients who fail early, maybe that’s a different kind of biological ballpark. This is something. It’s important to add [to] that portfolio to have new drugs coming up. As you mentioned, the fourth drug, it’s an option to improve maintenance therapy. Saying that to [wrap] up the first module, we need more markers. I think we need more clinical and biological markers to preselect our patient cohort, to show that we have the best treatment for all patients. I think that’s something we really have to learn in small [cell lung cancers]. It’s a very interesting field. What do you think, Laurent, for the first line, what would be the idea you have? What would you like to see as the next thing?

 I think our goal is to move in small cell lung cancer as we moved in non–small cell lung cancer, with proper identification of good patients for the good drug. We are far from that today, but I think we are moving forward, and so we have to work on that. It’s very important.

I think this is a good summary, thank you very much.

Before closing out their first module, expert oncologists consider novel treatment strategies and agents in the frontline setting of stage small cell lung cancer.

Novel and Emerging Frontline Treatment Strategies in SCLC

 To continue from here, we have real-world data from Spain. The Spanish colleagues very often have good registries and have a fine cooperation within Spain. What do you think about the CANTABRICO data which have been published?

 First of all, I would like to say that I’m very interested in this real-world data because it’s very important. Notably, in thoracic oncology, to make sure that the results from randomized clinical trials are still the same for the patients we are treating in routine practice. The CANTABRICO study [NCT04712903] is a phase 3b study. It’s a single-arm multicenter study that was conducted in Spain. The eligible patients were treatment-naïve patients with extensive-stage small cell lung cancer. There were performance [statuses] from 0 to 2, which is a difference with randomized clinical trials we mentioned before. These patients were treated with durvalumab, plus platinum [chemotherapy] and etoposide.​​ The total number of patients of the CANTABRICO study was around 100. It’s very interesting to note that the ASA, response rate, median PFS [progression-free survival], and safety outcomes were very similar to what was observed in the CASPIAN trial. Also, this randomized phase 3 trial, CASPIAN [NCT03043872], was conducted in selected patients. It’s very interesting to see that the real-world data confirms the results of the randomized phase 3 trial.

 Laurent, that’s very interesting. Would you think that, showing the real-world data, if you take 100 patients who have been treated with triple therapy, is there still the same kind of signal that there are some patients who have a very high benefit and there are some patients who have no benefit? Do you think this is something that we do encounter in this cohort of patients? Does triple IO [immunotherapy] work fine for everybody?

I agree with you. IO doesn’t work for everybody the same. Some patients experience benefits, [while] others do not experience any benefits and can experience toxicities. So we have to make it better in terms of patient selection, to select the good patients for IO, the bad patients for IO, and we have to improve our selection in the future, it’s absolutely necessary. What’s also interesting with real-world data is that we can more easily compare it with randomized clinical trials. We can more easily assess the role of the sequences of treatments, and to [choose] what treatment is given after the first line, and are there some sequences that are better for some patients and other sequences better for other patients? [With the] data from the real world, I think more interesting is that the results of clinical trials are always limited to 1 line of treatment.

 I think that’s an important part of our daily business to have registry data. But you mentioned toxicity. Overall, I personally see [that] toxicities associated with PD-L1 inhibitors like durvalumab or atezolizumab seem to be less aggressive and not as frequent as we do see with classical PD-L1 inhibitors like pembrolizumab. We do get more complex adverse events than we have seen with other first-line treatment in non–small cell lung cancer. In particular, we have also seen problems with CTLA-4 antagonists like ipilimumab, which usually are not a standard of care in small cell lung cancers. So toxicity is manageable because we now have a lot of expertise with PD-L1 inhibitors in our patients. The rate of pneumonitis or other [adverse] effects are not as bad as we anticipated. What’s really interesting is at the very beginning we thought that patients who had paraneoplastic syndrome would be very sensitive to the use of IO, but it’s the other way around. Obviously, they have a very active immune system, and they don’t really have a higher incidence or prevalence of problems, at least, what we have seen in our patients. We try to manage these patients. Maybe we have a better view [of] these patients. We watch these patients closer these days to make sure that these patients are under good control.

Laurent Greiller, MD, and Christian Grohé, MD, consider real-world data and adverse events observed with frontline chemoimmunotherapy in small cell lung cancer.

Real-World Data and Observed AEs With Frontline Chemo IO Therapy in SCLC

What would be interesting is to discuss if we have any predictive or prognostic biomarkers beyond the clinical one I was mentioning to guide our strategies. What do you think, Dr Grohé?

 In terms of understanding how we are going to treat these patients, you already alluded to the point that patients can present with a very poor [ECOG] performance status. If we can initiate treatment, they do better. Still, at our institution, Charité Comprehensive Cancer Center [in Berlin, Germany], 1 out of 5 patients do not make it to first-line therapy because they’re too sick. Their performance status…is 3 or 4. So this is an interesting issue. What would be the most important biomarker to help guide our treatment options? Honestly, there are a few. Maybe in standup care, something such as LDH [lactate dehydrogenase]. Sometimes if your patient has elevated liver enzymes, [you may] look for neuroendocrine markers, which are circulating. My personal belief is the clinical context is pretty much like it is with a hematology disorder. If you have a very high cell turnover, this is just an indicator of massive disease burden. This is basically what you’re looking for…. We might discuss a little bit later that small cell lung cancer [has] 4 different kinds of subtypes. This is part of the histology and the genetic analysis of the tumor, which does not play a role at the beginning of the first initiation of first-line therapy. We are still at the very beginning of using or having useful biomarkers for all patients with small cell lung cancer, in my opinion. I don’t know if you, Dr Greiller, share this opinion.

 I totally agree with you. It’s a subgroup of lung cancer patients in which we’re needing additional biomarkers because honestly, we don’t really have them today.

It’s a clinical decision, how to treat and when to treat. It’s pretty much an acute disease. Once we have the diagnosis, we should start.

Shared insight on the early but evolving role of biomarker testing in patients diagnosed with extensive- or limited-stage small cell lung cancer.

Small Cell Lung Cancer: What is the Role of Biomarker Testing?

 program titled “Evolving Paradigms in the Small Cell Lung Cancer Treatment Landscape.” I’m Dr Laurent Greiller, from Aix-Marseille University [in France]. I’m joined today by my esteemed colleague and fellow thoracic cancer expert, Dr Grohe, whom I would like to invite to introduce himself.

Hello to everybody. My name is Christian Grohé. I’m working in Berlin at Thorax Centre, which is part of the comprehensive cancer Charité Comprehensive Cancer Center [in Germany]. We specialize in both diagnostic algorithms and the treatment of patients with small cell lung cancer in part of all sorts of oncology unit. We are something like a 1-stop shop where you can do everything at the same time. I welcome everybody and thank you for joining us. We are going to discuss a number of recent updates in the treatment of small cell lung cancer that were presented at key conferences last year and this year. We will discuss the data in the context of the guidelines. We have the respective guidelines of the European and American guidelines, the treatment landscape, and its impact in clinical practice. In particular, what we can do in first-line treatment and how we are going to treat patients with refractory disease and data lines. Let’s get started.

We are starting this discussion with a module on the evolving treatment landscape for small cell lung cancer in the frontline setting. Dr Grohe, how does a patient normally present with small cell lung cancer?

This is a very good question of understanding why the outcome of all patients very often is so poor. Usually, patients with lung cancer can present with weight loss and fatigue. Some patients have hemoptysis and some have certain kinds of other clinical features like dyspnea. [Patients with] small cell lung cancer are an entity unto themselves. They can have fatigue and weight loss. Very often they present at the very later stage. What’s specific for them is that they can present with so-called paraneoplastic syndromes. Some of them have hypernatremia, low sodium that leads to dizziness or confusion. Some of these patients have other very fascinating features. This particular small cell lung cancer, because it’s neuroendocrine, has a mixture of classical internal medicine problems and sometimes neurologic problems…. How do we define these patients? Is there a difference in terms of [American Joint Committee on Cancer] TNM staging, or is there another way of formatting these patients, such as limited or extensive stage? How are we going to do this?

 For historical reasons, there is this old classification for patients with limited or extended stage small cell lung cancer. The limited stage is defined as the tumor being confined in 1 hemothorax and the lymph nodes. In other terms, patients can be eligible for radiation therapy, and all the others are classified as extensive stages. Even if TNM staging is now recommended scientifically, it is all classification with limited stage and extensive stage. It’s the one we are used to every day in routine practice. This is an important aspect for the prognosis of this patient. Of course, patients with limited stage disease have better prognosis compared with patients with extensive stage cell lung cancer. But there are also prognostic factors that we have to take into consideration, such as age, [ECOG] performance status, weight loss, and the comorbidities that are frequent in this population of heavy smokers. We are also looking at biological prognostic parameters that we can have in routine practice such as elevated LDH [lactate dehydrogenase] or low sodium. For example, [there is] the syndrome of inappropriate antidiuretic hormone secretion, which is a paraneoplastic syndrome, as you talked about before.

 I think this is very important to understand that the classification we do, limited and extensive, is based on our belief or anticipation, which might be prognostic. Some patients these days have had a PET/CT scan. Does that play a role in small cell lung cancer in terms of understanding what is limited or extensive and do we recommend that? Does it play a role in clinical practice?

 I think that since we are using PET/CT in the diagnostic work-up for this patient, we are seeing a more extensive stage than before. So the question is, is this classification still relevant today? I’m not sure, but in practice we are often using this one.

I think it’s still very important. Particularly because we consider radiotherapy an important part of the treatment options for our patients with limited disease. In terms of factors that influence prognosis, what do you think is the most important feature when we look at these patients to understand the prognostic value?

It’s clear that we have more and more elderly patients and that somehow age is important. Performance status is important, but compared with non-small cell lung cancer, we know that patients with poor performance status can really benefit from chemotherapy. For example, patients [with a performance status of 2], which is not so clear in non–small cell lung cancer without actionable molecular alteration. Comorbidities are very important. As I mentioned before, this is a population of heavy smokers, and these patients have other diseases and lung cancer. They have COPD [chronic obstructive pulmonary disease] and they have heart disease. All of these comorbidities have to be taken into account for the [treatment] of these patients.

Expert oncologists Laurent Greiller, MD, and Christian Grohé, MD, make introductions and review the current paradigm for small cell lung cancer diagnosis and classification.

Christian Grohé, MD

Articles

Small Cell Lung Cancer: What is the Role of IO Therapy in the Frontline Setting?

Overview of Frontline Treatment Options in Small Cell Lung Cancer

Novel and Emerging Frontline Treatment Strategies in SCLC

Real-World Data and Observed AEs With Frontline Chemo IO Therapy in SCLC

Small Cell Lung Cancer: What is the Role of Biomarker Testing?

Current Strategies in Diagnosis and Classification of Small Cell Lung Cancer