 What do you think is going to change the clinical practice in the next couple of years in small cell lung cancer, whether it’s limited or extensive stage? Anne, feel free to say it’s your ipilimumab-nivolumab study in that group. Don’t be shy about it.

 Great question. There are a couple of things that are really exciting. We just had results from the IMpower010 trial regarding adjuvant atezolizumab for early-stage cancers. Interestingly enough, in recent months, I’ve seen a number of incidentally found patients with early-stage small cell lung cancer who have undergone resection for early stage disease. There may actually be a role for surgery followed by adjuvant I/O [immuno-oncology]. I certainly think with the more liberalizing of the US Preventive Services Task Force indications for low-dose screening CT, we might see a few more early-stage small cell lung cancers being diagnosed. That’s 1 thing.

I agree with folks talking about the molecular subtypes. We’ll be potentially looking at the Lung-MAP trial or an adaptive clinical trial strategy that helps randomize or sort patients by their molecular subtype for a certain therapeutic strategy. Also, stay tuned for the ipilimumab-nivolumab or the anti-CTLA4 PD-1 results. We’re going to make strides in understanding the biology of small cell lung cancer. We’re going to hopefully understand more about what determines response to checkpoint inhibitors. Perhaps it’s as simple as getting those T cells in to make a difference. I do think that the holy grail for small cell lung cancer in some ways is being able to treat it like EGFR, as different subtypes that have different therapeutic approaches. Understanding more about the biology will help us understand the disease and help the patients.

 Thank you, Anne. That was wonderful. Wade?

 I’m going to go with consolidative checkpoint inhibitors in limited-stage disease, and I’d like to interject a personal research interest. I hope that blood-based assays of circulating tumor DNA can best inform patient selection, ideally linked to subtype. Hopefully you hear much more from me in the years to come about that.

 We’re looking forward to it. Thank you. Vivek?

I completely agree with what Anne and Wade said. We need more effective strategies for each of these subgroups in clinical trials. More patients should be enrolled in clinical trials, especially in the first-line setting, second-line setting, and third-line setting to answer these questions. As I said earlier, the small cell lung cancer field is about 15 years behind the non–small cell lung cancer field. I’m sure there’s going to be a future renaissance of biomarkers and personalized therapy. Defining the subsets in small cell lung cancer represents the first step in our understanding of what drugs work best for which patient, at least preclinically. It at least gives us a guide for a path forward for personalized approaches for small cell lung cancer.

One of the main challenges we face in small cell lung cancer and any small cell tumor with neuroendocrine phenotype or genotype is that they often quickly develop resistance to treatment, even after the initial response. To determine what causes resistance, we need to also study the biology of the resistance mechanisms. We’ll understand the response mechanisms, of course, but the key is to understand the resistance mechanisms in these patients. I want everyone in this field to come together to define biomarker-driven clinical trials and also participate in co–clinical trials and PDX-driven co–clinical trials to understand the resistance mechanisms so that this may guide us for precision therapies in the future. We are hopeful. Thank you.

 Thank you. Stephen, we’re going end it with you.

 The most immediate change will be radiation. As Wade said, in limited-stage disease, it’s a slam dunk. I also think the consolidative radiation therapy in extensive-stage disease will probably be positive as well in the right subset. Adding radiation will be big. We’ve got new drugs, including nal-IRI [nanoliposomal irinotecan] and AMG 757. These are going to be impactful drugs.

We’re going to see some of the old drugs make a comeback when we start using them in the right way. When we start using them with biomarkers, we’re going to see Aurora-A kinase inhibitors and maybe MMP. We’re going to see these old drugs find a home. We were just using them wrong. I’m hoping that 10 years from now, the biggest change will be less small cell lung cancer. Unlike a lot of other cancers, small cell lung cancer is largely preventable with smoking cessation. This is 1 where we can make an impact in preventive medicine as well.

 Thank you so much. Thanks to all of you for this wonderful and informative discussion. Thank you for your final thoughts on where we’re going in small cell. Those are all really great thoughts. I’d also like to thank our viewing audience. We hope that you found this 

® discussion to be useful and informative. Thank you.

Videos

Panelists conclude their discussion by commenting on areas of unmet need and sharing personal perspectives on factors that may change clinical practice for SCLC in the future.  

Future Directions in Treatment of Small Cell Lung Cancer

Wade, what do you think about DLL3 bispecifics? Where do you think they’re going? Do you think these are promising data we’re beginning to see? How do you put it in context?

I’d place it along similar lines of a subset of patients having a notable benefit. I hope more patients can be enrolled and treated with these DLL3 bispecific T-cell engagers and that we have meaningful identification of patients with durable response. Treating everybody with it is going to be a hard sell in relapsed small cell lung cancer [SCLC], just because of the performance status and comorbidities of most of the patients.

 Vivek, do you think molecular targets are going to have any meaningful role in small cell lung cancer?

 Absolutely. Thank you for that question. As lung cancer doctors and oncologists, we all know that non–small cell lung cancer has become the poster child for precision oncology. As a field, small cell lung cancer is about 15 years behind non–small cell lung cancer. Hopefully there’s going to be a renaissance of biomarkers and personalized therapies. One of the first steps is defining the population. Everyone here mentioned the recent subclassification. Although the previous studies identified 3 possible subtypes of small cell lung cancer based on transcription factors, which indicate whether a particular gene is turned on or off, a large number of patients with small cell lung cancer don’t fit into 1 of these 3 groups.

Rather than trying to apply a hypothesis to the many tumors, Lauren Byers looked into an unbiased bioinformatics approach, letting the data speak for itself. This led to 1300-gene signature that comes from the previous subgroups, SCLC-A, SCLC-N, and SCLC-P. Interestingly, they came up with another unrecognized fourth group with a unique new landscape, as Steve Liu mentioned. What are the 3 subgroups? The first group is SCLC-A, which is activation of 

. The second group is SCLC-N, which is activated by 

. The third group is SCLC-P, which is activated by 

. The fourth and most important type is the SCLC-I group, or the SCLC-inflamed group, which is categorized by an inflamed gene signature with high expression of multiple immune genes, including significantly greater levels of genes, indicating the presence of CD83-positive cytotoxic T cells.

This shows that the inflamed group has a distinct biology and a tumor microenvironment that tends to be more responsive to immunotherapy. Interestingly, they also suggested the SCLC-I group was sensitive to immune checkpoint blockade; the SCLC-A group, the ones with activation of the 

 pathway, responded better to the BCL2 inhibitors; the SCLC-N group responded preclinically to Aurora kinase inhibitors; and the SCLC-P group responded to the PARP inhibitors. This and other studies give us hope that the field of small cell lung cancer is looking to the field of non–small cell lung cancer and that in the near future, we can identify subsets of patients who will benefit from therapy. We’re all hopeful that small cell lung cancer is going to be defined by precision oncology.

Key opinion leaders in lung cancer share personal thoughts on the potential for bispecific agents and the overall impact of inhibiting molecular targets.

Emerging Treatments in SCLC: Impact of Targeted Therapy  

 Anne, we have a couple of studies. There was a study targeting PP2A with a drug, LB-100. There are some data regarding the combination of immunotherapy and lurbinectedin. Could you comment on those studies?

 Sure. There aren’t any results, but I can talk a little about the study designs. When we’re starting out with our standard of care, which is chemotherapy plus I/O [immuno-oncology], what can we do to better that? One idea is to add something to it. That’s the case for the LB-100 study, where the premise is the addition of a protein phosphatase 2A inhibitor to our standard of care up front. It’s basically a phase 1b open-label study. The patients receive LB-100 IV [intravenously] over 15 minutes on days 1 and 3, and atezolizumab and carboplatin-etoposide, which we normally give.

The rationale behind this is that because the PP2A inhibitors work in combination, there are good preclinical data that show they’re effective chemotherapy and radiation sensitizers, either with cisplatin or doxorubicin. Ultimately, what happens is that the use of this in combination with chemotherapy lowers the cell cycle arrest and ends up in mitotic catastrophe and more cell death. There’s also possibly an increased vascular permeability aspect of it. But the idea behind that trial is to ask, is it safe? Are we adding additional toxicity? Hopefully not. And can we improve upon the efficacy of that regimen?

The other trial is basically ipilimumab-nivolumab and lurbinectedin. This is a single-arm phase 1/2 trial to determine the MTD [maximum tolerated dose], the recommended phase 2 dose, and safety and efficacy. The outcomes are response rate, progression-free survival [PFS], and overall survival [OS] in the phase 2 portion. This is for relapsed recurrent small cell lung cancer. This helps us provide an option for our patients that is combination chemotherapy-I/O.

From the non–small cell realm, if you have combination chemotherapy-I/O up front, then what do you do? You’re using chemotherapy alone. There are some trials asking whether you can add chemotherapy postprogression, but this would be a trial where you could look at the combination chemotherapy plus I/O after you use that up front. We talked at length about lurbinectedin and the combination anti-CTLA4 and PD-1 approach that might allow our patients to get an effect, although you’d have to look carefully at the toxicity of that regimen.

 Great. Thank you, Anne. Stephen, since we’re talking about emerging therapies, there’s also a lot of movement in limited-stage disease. There are at least 3 trials with very similar approaches, perhaps checkpoint inhibitor plus chemotherapy–RT [radiotherapy]. Please update us on those.

 This will be potentially transformative for this subset. These all look great. Limited-stage makes up about a third, maybe a little less, of small cell lung cancer. We know that chemotherapy-radiation given concurrently is potentially curative. As we’ll all attest to, while cure is our goal, it’s not necessarily our expectation, because we achieve that in only maybe 20% to 30% of people. The promising strategy is to combine immunotherapy in this setting. It’s building on the rationale that supports the PACIFIC trial, our standard of care in unresectable stage III non–small cell lung cancer. We know I/O adds benefit to small cell lung cancer, based on the studies we’ve talked about. We know that it can improve outcomes after chemotherapy-radiation, based on PACIFIC. So this really was low-hanging fruit.

ADRIATIC is a randomized phase 3 trial. It’s looking at consolidation immunotherapy, structured in a similar way to PACIFIC. You finish chemotherapy-radiation and then randomize to standard observation, or durvalumab, or durvalumab plus tremelimumab. We’ll see if this context can find tremelimumab a home. We know tremelimumab is not beneficial in extensive-stage disease, but maybe this is a different therapeutic index. This is a big study, with over 700 patients, with PFS and OS end points. It’s a very important study.

Another similar trial is an NCI [National Cancer Institute]–sponsored study, NRG-LU005. That’s looking at concurrent chemotherapy-radiation with atezolizumab delivered during the chemotherapy-radiation vs chemotherapy-radiation alone, then atezolizumab vs placebo maintenance therapy. We know from data out of [The University of Texas] MD Anderson [Cancer Center] from Steven Lin that giving atezolizumab with thoracic radiation appears to be safe. Is there synergy by introducing that earlier? If we think back to the PACIFIC subsets, where patients who got durvalumab a little closer to radiation maybe did a little better, would there be more rationale to give atezolizumab with radiation? We’ll see. This is a study of over 500 patients. The phase 2 is looking at PFS as the end point, but it’s the phase 2/3 that will look at OS.

KEYLYNK-013 is a little more complex. This is looking at standard chemotherapy-radiation vs delivering pembrolizumab with chemotherapy-radiation and continuing pembrolizumab maintenance vs delivering pembrolizumab with chemotherapy-radiation, pembrolizumab maintenance, and olaparib maintenance. It’s looking at that PARP/PD-1 synergy, largely work from doctors Triparna Sen and Lauren Byers at MD Anderson. It’s intriguing to see if there’s some relationship between these 2. The biomarker data that are going to emerge from all these studies will hopefully inform our decisions a little more. At least 1, or maybe all 3, of these studies will end up being positive. It’s almost a race to see which will be positive first. There are very exciting things to come for limited-stage small cell lung cancer.

 KEYLYNK-013 is not selecting patients based on any biomarker for olaparib. It’s just all-comers at this point, correct?

 That’s correct. None of them is selecting patients by biomarkers. We’re still very much in the infancy of biomarkers. It’s still discovery right now. We’ll see if that leads to subsequent studies that need to be validated as integral. But to start with, it’s just discovery.

Anne Chiang, MD, PhD, reviews the study design of 2 clinical trials, adding a third agent to the standard-of-care regimen of chemotherapy plus I/O; Stephen Liu, MD, discusses clinical trials in limited-stage disease.

Emerging Treatments in SCLC: Triplets + Limited-Stage Disease

 Vivek, do we have some data on targeting DNA-damage pathways?

 Absolutely. We know that Temodar, or temozolomide, and PARP inhibitors are active in small cell lung cancer. The first study I’m going to discuss is a randomized double-blind phase 2 trial of temozolomide in combination with either a PARP inhibitor, veliparib, or placebo in patients with sensitive relapsed or refractory small cell lung cancer. This phase 2 randomized study evaluated whether the addition of a PARP inhibitor, veliparib, or temozolomide improves a 4-month progression-free survival [PFS]. They entered 104 patients with recurrent small cell lung cancer. They were randomly assigned 1:1 to either oral veliparib or placebo at 40 mg twice daily, days 1 through 7, and oral temozolomide 150 to 200 mg for days 1 through 5 of a 28-day cycle until disease progression.

Response was determined by imaging at week 4, week 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Unfortunately, no significant difference was seen in the 4-month PFS between temozolomide plus veliparib and temozolomide and placebo. The 4-month PFS was 36% and 27%, respectively. Unfortunately, median overall survival was not ultimately improved significantly with temozolomide and veliparib. However, they saw a signal with an objective response rate significantly higher in patients receiving temozolomide and veliparib when compared with placebo. Grade 3 and 4 thrombocytopenia and neutropenia were more common in the combination arm with Temodar and veliparib: 50% vs 9%, and 31% vs 7%.

The most important part of this interesting study was this biomarker analysis, which significantly prolonged the PFS at 5.7 vs 3.6 months, and the overall survival of 12.2 vs 7.5 months, when observed in a subset of patients with 

-positive tumors treated with temozolomide and veliparib. Look for this biomarker. More is known right now about this biomarker, 

-positive tumors, and there are more agents and trials that are going to be targeting this biomarker and similar biomarkers in this space.

The second study I was asked to look into was the clinical efficacy of a PARP inhibitor. The second 1 was olaparib as monotherapy or in combination with an ATR inhibitor. It’s an AstraZeneca agent called AZD6738, which is ceralasertib. Using these 2 small molecules that target the DNA-repair pathway—the PARP inhibitor olaparib in combination with the ATR inhibitor ceralasertib—the investigators evaluated the clinical efficacy of olaparib monotherapy or combination in patients with relapsed small cell lung cancer.

This is a part of a phase 2 biomarker-driven umbrella study in small cell lung cancer, the SUKSES study. Patients who failed prior platinum therapy were allocated based on their genomic alterations. Patients with mutations in the HR [hormone receptor] pathway mutation, but not limited to 

 mutations, were allocated to olaparib monotherapy, which is the SUKSES-B arm. Patients in a biomarker nonmatched arm in the group of unselected patients were also allowed to receive olaparib and the ATR inhibitor. It was called the SUKSES-N2 arm. The primary end point was objective responsive rate. Simon’s 2-stage design was used. What did they see? Unfortunately, both arms were terminated at stage I based on predefined protocol criteria. In the olaparib monotherapy arm, the objective response rate was 6.7%, and the disease control rate was 26.7%, with 1 partial response and 3 stable diseases. The median progression-free survival was 1.25 months, and the median overall survival was 8.56 months.

A patient was reported to have a confirmed partial response with a tumor volume decrease of 37% compared with baseline. Interestingly, a splicing side view vision of the 

 was identified from deep target sequencing in this patient. In the combination arm, the objective response rate was 3.8%, the median PFS was 2.75 months, and the overall survival was 7.18 months. Unfortunately, 3 patients discontinued treatment because of grade 5 pneumonia and grade 3 drug-induced pneumonitis. Targeting DDR [DNA damage response] pathways with olaparib as a single agent, or in combination with this ATR inhibitor, demonstrated some early signal of activity in these patients. There wasn’t much, but we think there are definite signals of activity.

What did we learn from this trial? It’s important to note that this is the first biomarker-driven umbrella trial in small cell lung cancer. Targeting DDR pathways with olaparib as a single agent or in combination with an ATR inhibitor demonstrated some signal of activity in these patients. Unfortunately, it didn’t pan out in the big picture. But I personally advocate for further investigation of these drugs in combination with other agents, like an anti-VEGF agent, which are ongoing, like olaparib and bevacizumab, and olaparib and avelumab. We look forward to studies with multiple combinations in specific biomarker-driven subsets of this population.

What do we come back to? As we all know, small cell lung cancer has been treated as a single disease because the tumors all look similar under the microscope, even though they behave very differently. As Steve mentioned, the study from Carl Gay and Lauren Byers from [The University of Texas] MD Anderson [Cancer Center] provides a transformative new system to define the 4 major subtypes of small cell lung cancer. It’s 1 of the first avenues for personalized treatment for the second most common type of lung cancer, small cell lung cancer. We look forward to such elegant biomarker-defined studies in the future to guide us in further treatment.

Thoracic oncology expert Vivek Subbiah, MD, provides an overview of recent clinical trials studying agents targeting DNA damage for the treatment of small cell lung cancer.

Emerging Treatments in SCLC: Targeting DNA Damage

 Wade commented that he doesn’t think there are many people who wouldn’t be able to get immunotherapy. Stephen, you started your discussion by presenting the real-world data regarding patients who have PS2 [performance status 2] and brain metastases. Wade, if you have someone with extensive-stage small cell lung cancer and they’re in a hospital, just like Stephen suggested—which is what we see for the most part—and you have identified brain metastases, but they’re asymptomatic, what is your preferred method of treating these patients?

 I would start patients with asymptomatic brain metastases on combination chemotherapy-immunotherapy and then address the brain metastases among the radiation oncologists. There is more of a push to consider SRS [stereotactic radiosurgery] for patients with small cell with brain metastases. Whereas, historically, whole brain radiotherapy had been a broad recommendation.

Institutionally and logistically, getting immunotherapy approved for an inpatient can be a hurdle. It has been an initiative that we’ve typically pursued to make that happen. That’s where working with our pharmacy and formulary colleagues has been instrumental. Ultimately, we don’t know for sure whether 1 dose of immunotherapy in cycle 1 as an inpatient is going to make a difference. But hypothetically, we would like to include it to maximize the immune response at the time of initial response.

 Vivek, what do you do when you have somebody with brain metastases with this diagnosis?

 We would discuss it in a multidisciplinary group meeting. It’s individual case-based. I primarily focus on patients in clinical trials, so all these patients we discuss in the context of multidisciplinary care. I agree with Wade. It depends on the patient, insurance, how quickly we can get these agents approved, and the clinical condition of the patient. It’s individual discretion and discussion with every patient.

 Stephen, you mentioned some potential new biomarkers and the transcription data that have come out, basically dividing small cell into 4 separate categories. Can you comment a little more about that and any other efforts you’re aware of regarding a potential biomarker for this disease predicting immunotherapy or chemotherapy, sensitivity resistance, or anything in that category?

 The transcription subset data are very intriguing. We’re looking at some heterogeneity in small cell. While we treat all small cell essentially the same, we know there are different behaviors. We all see this in our clinics. There are some patients who do quite well for a long time. When we look at some of these data presented early on from Charlie Rudin, [MD, PhD,] and John Heymach, [MD,] and then updated later with Carl Gay, [MD,] Triparna Sen, [PhD,] and Lauren Byers, [MD], there seem to be specific subsets based on expression of transcription regulators. These are useful, because while the original data are mostly based on RNA sequencing data, for a lot of these, we can detect these subtypes based on immunohistochemistry [IHC]. Not so much the inflamed group, which isn’t really the expression of a specific transcription regulator—more the absence—but we can check 

One of the challenges with biomarker development in small cell is that the tissue samples tend to be small, fine needle aspirates, cytologic specimens because it’s a central disease often diagnosed by bronchoscopy, or EBUS [endobronchial ultrasound], so we don’t have a whole lot of tissue. You don’t need a whole lot of tissue to make the diagnosis of small cell. It’s pretty characteristic under HNE [4-hydroxy-2-nonenal], but in order to do these biomarker studies, it’s hard to get these big chunks of tissue, which is how we made a lot of advances in non–small cell lung cancer.

It’s hard to get this tissue, and it’s a fulminant disease course. Patients can’t stick around too long, go back, and get repeat biopsies. They need to move forward with therapy. The natural history is not forgiving at all, so it’s difficult to rebiopsy. We have to make do with what we have. If you’ve got a frontline study that’s randomizing or stratifying by specific biomarker, you can’t wait a few weeks to get RNA sequencing data. You can’t wait a few weeks to get next-generation sequencing data. If IHC is quick, it’s possible, so it introduces that as a biomarker. There’s a lot of promise, but we still have a long way to go.

With that said, when we look at Impower133 and these transcription regulator subsets, we see that the inflamed subgroup seems to derive relatively more benefit and long-term survival with atezolizumab. But we see long-term survival in nearly all of the subgroups, with maybe the exception of 

 that’s a pretty rare one. So we can’t use that to select patients. It’s not nearly ready for prime time. It’s encouraging, but there are a lot of challenges, including heterogeneity.

 Well said. Thank you. Those are really important aspects of caring for patients with metastatic small cell that we need to keep in mind. Anne, I have 1 final question for you. In the 2 randomized studies we talked about, the checkpoint inhibitor in question was given every 3 weeks in one and every 4 weeks in the other. Do you see any major difference between the frequency of administration of the checkpoint inhibitors?

 No. Actually, can I speak to the biomarker question?

 It’s important for people to realize that PD-L1 in small cell is different from in non–small cell. If you look at tissue microarray studies that have been published in the literature, you’ll have one that has 92 specimens that are all 0% PD-L1–positive in the tumor. In fact, for the KEYNOTE-028 trial, they had to expand that definition of positivity to include not only the tumor cells, but the macrophages and the TILs [tumor-infiltrating lymphocytes] to get a combined positive score [CPS] of roughly 40%. And then when you looked at the ones who were positive, they showed a higher response rate of about 35% vs 6%. It’s a different story. It’s not just PD-L1 on the tumor. It’s the microenvironment that’s important. That’s where the tissue is important, because we’re going to have to be able to understand what it is that allows those checkpoint inhibitors to help make a response.

With respect to the frequency, the pandemic has showed us a lot about frequency of administration. During COVID-19, a lot of institutions, ours included, went to an every-6-week administration of pembrolizumab. For atezolizumab, we’ve been doing every 4 weeks. I don’t think the frequency of administration is going to make a big difference.

With regard to our inpatients who are diagnosed with small cell, it’s positive that the pharmaceutical industry went to CMS [Centers for Medicare & Medicaid Services], and the inpatient use of checkpoint inhibitors for extensive-stage small cell is something that will now be reimbursed to some extent. Making that happen within your own hospital, through whichever formulary and so forth, is important. We’re still working on that. We don’t know whether those 1 to 2 extra doses are going to make a difference, but the general approach toward this disease has been to try to use all your guns up front because we think that’s probably our best chance at affecting and improving these patients’ survival.

 If I can clarify what Anne said; anything about the biology and making care better, I agree with. But we shouldn’t be using PD-L1 today to select because, in KEYNOTE-604, they looked at the CPS, and there was no difference between 1% greater or negative. It’s…for PD-L1, but it’s not yet ready for use.

 That was going to be my question. Is anybody checking for PD-L1 at this point to make a treatment decision? I’m not.

 There’s no clinical utility for it. It’s not just a matter of reimbursement. There are no data to support its use. I don’t think it matters whether it’s reimbursed at this point, because what are you going to do with the data? It’s the same thing with TMB [tumor mutational burden] in small cell as far as I’m concerned. Outside of a clinical trial or a research question, there really isn’t a role for any of these biomarkers right now. Unfortunately, we’re left not knowing who truly benefits from these drugs and who doesn’t. Wade, where do you think we’re heading? How do you see the treatment landscape changing in the coming years?

 One of the most ambitious and I hope ultimately fruitful hypotheses is linking the combination of our transcription factor-defined subsets in areas of opportunity. With extensive-stage small cell lung cancer, I would argue that’s the maintenance setting. Once we have a response with platinum doublet and immunotherapy, can we identify how to best capitalize and consolidate those gains with a subset-directed therapy? Dr Byers, in one of her most recent papers, articulated that very well in the conclusion. We have a way to go, but one of the biggest ambitions in extensive-stage disease is trying to consolidate gains in the maintenance setting.

 Do you see any new treatment options coming down that we should expect to see or would be effective in the frontline setting?

 The biggest item I’m monitoring is the consolidated checkpoint inhibitor in limited-stage small cell lung cancer. There’s nothing immediately in the next 6 to 12 months that I’m anticipating in the extensive stage frontline setting. There’s maintenance PARP inhibitor use, which will be interesting to see. It’s not subset-selected, but it will be interesting to see how those data play out.

Panelists reflect on treatment considerations for asymptomatic brain metastases, progress in biomarker research, and frequency of administering checkpoint inhibitors.

Future Directions in ES SCLC

What do you use in your clinic? How do you choose who can get immunotherapy? Is there a patient in whom you know you’re not going to offer immunotherapy to? Can you go through your working diagnosis and everything else when you see someone in the clinic?

 Absolutely. I approach first-line therapy in patients with extensive-stage small cell lung cancer as if chemotherapy-immunotherapy is the standard of care for all of them, unless they have severe underlying autoimmune disease, which I would define as having visceral organ damage requiring more than 10 mg of systemic glucocorticoids per day for maintenance. It’s been interesting to watch in the field, particularly within thoracic medical oncology, the expansion of immunotherapy to these populations with underlying autoimmune disease. It seems like every 6 months, there’s another study demonstrating that we can safely offer immunotherapy to patients with underlying autoimmune disease with adequately close surveillance for immune-related adverse events. There’s also the compelling line of inquiry in the field regarding the improvement in tumor control in patients who develop immune-related adverse events.

More and more, we’re expanding the cohort of patients in whom we offer chemotherapy-immunotherapy. I approach atezolizumab and durvalumab as equivalent. It would be an interesting discussion among the panelists to see if there’s anything to the tail of the curve with durvalumab or any differences others feel between the 2. But for the most part, chemotherapy-immunotherapy for all patients.

Let’s talk about the tail of the curve. It’s all the discussion now. Stephen, as 1 of the authors and presenters of 1 of the studies, what do you think of the data Anne was talking about regarding the tail of the curve? Then I’m going to go around the room and ask each of you to comment on what you think the role of CTLA4 inhibition is when it comes to small cell [lung cancer].

 I agree with everything Anne said, but I don’t think there’s a role for CTLA4. When I look at the tail of the curve, you’re right that the tail looks better in the durvalumab-tremelimumab arm and almost catches up to the durvalumab tail. I feel like that’s because of the durvalumab, and that the only thing tremelimumab is adding there is cost and a heck of a lot of toxicity. To me, there’s no role for CTLA4 in small cell [lung cancer].

We saw in CheckMate 032 that nivolumab-ipilimumab was capable of inducing some long-term responses, but in the follow-up randomized portion of CheckMate 032, the nivolumab-ipilimumab didn’t do anything more than the nivolumab alone. There was probably a lot of selection bias in those early nivolumab-ipilimumab studies. Ipilimumab was removed from the NCCN [National Comprehensive Cancer Network] Guidelines based on that randomized trial in CASPIAN. That tremelimumab arm was disappointing and added a lot of toxicity. It almost caught up at the end, which is reassuring, but I don’t know that tremelimumab is adding much there. We’ll see if that changes with future studies. But even though the tail is what we focus on, I didn’t see a lot of difference in the durvalumab-alone tail compared with durvalumab-tremelimumab. That direct comparison wasn’t part of the formal statistical plan, but as of now, you’re going to need to convince me there’s a role for CTLA4.

 I agree with you. The durvalumab was clearly positive. That’s what we use now. I’m not convinced of the role of CTLA4 right now. The CheckMate-451 trial with maintenance I/O [immuno-oncology] didn’t tell us more. That being said, I do have an IIT [investigator-initiated trial] looking at ipilimumab-nivolumab in relapsed populations; especially patients who have gotten maintenance atezolizumab. There may be a signal there. In this trial, we’re doing pretreatment and on-treatment biopsies. There’s something to be said for looking at the tumor microenvironment and specifically the infiltration of T cells, so stay tuned for that. There may be a way anti-CTLA4 may help juice up the microenvironment so that we get T cells in there so we can have a response. That being said, for the general population, I don’t think there’s a role for anti-CTLA4.

Thanks, Anne. Vivek, what do you think about CTLA4? Do you think it has a role?

 I agree with Stephen. There’s a tail end, and there’s a tail end. There are no compelling data to show that CTLA4 does something. It brings added toxicity without much clinical benefit. The community especially would definitely not favor CTLA4. Good luck finding a good biomarker for the patients in whom CTLA would benefit. That would be a sub-substudy. It would be great to find a definite biomarker in a subset of the patient population who benefits, but with the data we have, I don’t see a benefit of adding a CTLA4 to this.

 It has no role, but I would absolutely love to see the subset of patients who are going to have prolonged benefit identified. The infiltrating lymphocytes are the way to go. There are associations with immune-related adverse events and neurological paraneoplastic syndromes in these patients, so it’s the right population to study.

There might be a biomarker there for CTLA4. We just haven’t identified it. Hopefully we can shed some light on it. Anne, what do you think of cisplatin vs carboplatin in extensive-stage small cell? Would you say there’s a huge difference when it comes to choosing cisplatin vs carboplatin?

 If we look at trials in the past, for the most part, carboplatin is fine. We’re talking about patients where we’re running a marathon. This is a disease that’s not curable. We want to provide our patients with the best quality of life they can achieve. That being said, for some select populations and for young patients who are very functional, I might consider cisplatin. But for the most part for extensive-stage [lung cancer], I would use carboplatin.

Panelists reflect on key points from recent studies in ES SCLC by discussing patients for whom immunotherapy may be appropriate, examining the role of adding CTLA4 inhibition to a PD-L1 inhibitor, and reviewing factors to consider when deciding between cisplatin or carboplatin.

Treatment Considerations: Chemotherapy + IO in ES SCLC

Anne, CASPIAN is another study. It was first presented in 2019 and updated in 2021. It also has some data regarding biomarker analysis. I was wondering if you could shed some light on that topic.

 Sure. The CASPIAN trial was similar to IMpower133. This phase 3 trial had about 800 patients with extensive-stage small cell lung cancer. They were randomized 1:1:1 for chemotherapy, chemotherapy plus durvalumab, and chemotherapy plus durvalumab plus tremelimumab, an anti-CTLA4 inhibitor. The first results presented for CASPIAN showed benefit similar to the IMpower133 trial. It was a positive trial, specifically chemotherapy plus durvalumab vs placebo. The median overall survival was 13 months vs 10.3 months. The hazard ratio was 0.73. It’s very similar to the atezolizumab data, which made everybody feel a little better. It was approved by the FDA shortly thereafter.

The differences between this trial and the previous trial included the fact that patients were allowed to be treated with cisplatin and carboplatin investigator choice. They could receive up to 6 cycles of chemotherapy. Asymptomatic brain metastases were allowed in these patients, which reflects what we see in the real world. There are a lot of patients with brain metastases that we unfortunately sometimes have to exclude from our clinical trials. It also allowed patients who had gotten PCI, or prophylactic cranial irradiation.

The most recent update by Jonathan Goldman and colleagues was in 

 and it showed the results from the durvalumab-tremelimumab arm, which was not positive. There was no difference in overall survival there. However, they note in their paper that the tail of the curve may be where the story is. In other words, although there wasn’t a difference in the overall survival, if you look at 12 months out at the landmark analysis, or even 24 months out, there are a significant number of patients surviving.

If you combine both the durvalumab and the durvalumab-tremelimumab arms and look at patients who have received I/O [immuno-oncology] in combination with chemotherapy at 1 year out and perhaps even longer, about 20% of them are surviving compared with about 5% in the chemotherapy-only arm. Perhaps there’s something there about the tail of the curve. It is of note that only about 60% of the patients were able to get the full 5 planned doses of tremelimumab, so perhaps the actual survival benefit was somewhat attenuated. But there does seem to be some long-term benefit for a subset of the patients. That goes back to what Steve was talking about: How can we figure out which of those patients can benefit?

At the 2020 ESMO [European Society for Medical Oncology] Virtual Congress, Jonathan Goldman and colleagues showed a further analysis of the CASPIAN trial. They looked at patients whose progression-free survival [PFS] was greater than 12 months or less than 12 months. Of course, you’d imagine that the people who are in the greater-than-12-months group do better than the others. But they saw a difference in a number of aspects. For example, the patients who were in the greater-than-12-months PFS category actually had a median of 25 cycles of durvalumab, compared with 7 in the poor PFS category. The patients who were in the better PFS—greater than 12 months—category had an overall response rate of 96% compared with 63%. Their overall survival at 2 years was 77% compared with 11%. That’s saying if you’re going to do well, you’re going to do really well. Unfortunately, if you’re going to do poorly, you’re not going to do well at all.

The other big aspect of that abstract was that TMB, tumor mutational burden, was not helpful in determining prognosis. Going back to the CheckMate 032 trial looking at nivolumab and nivolumab-ipilimumab in TMB, we were all very excited about patients who got nivolumab-ipilimumab who had high TMB and had an overall response rate of about 46%. That didn’t pan out in the IMpower133 trial. Whether or not you used a cut point of 10 or 16 mutations per megabase, that wasn’t predictive of response. TMB is not the marker here. We’ll have an interesting discussion about what we think might be a marker. But that’s basically the results of CASPIAN and what’s happened since then.

Thank you, Anne. I appreciate it. Those are a lot of good points to come back to during our discussion.

Thoracic oncologist, Anne Chiang, MD, PhD, reviews the trial design and results of the CASPIAN trial and emphasizes implications for long-term benefit of combining platinum chemotherapy with durvalumab.  

First-Line Therapy in ES SCLC: CASPIAN

® titled “Evolving Approaches in Small Cell Lung Cancer.” I’m Hossein Borghaei, a thoracic medical oncologist at Fox Chase Cancer Center [in Philadelphia, Pennsylvania]. Joining me in this discussion are my colleagues, all of whom are experts in the field of lung cancer and in clinical research: Dr Anne Chiang, Dr Wade Iams, Dr Stephen Liu, and Dr Vivek Subbiah. We’re going to discuss a number of topics pertaining to the use of systemic therapy in patients with small cell lung cancer. We’ll discuss the latest research in the field and the impact of recent clinical trials on making decisions around these treatment decisions.

This program is going to have 3 separate sections. Let’s get started on our first topic: the role of first-line therapy for patients with extensive-stage small cell lung cancer. We decided ahead of time to go based on our first names, so I’m going to start with Stephen. Can you bring us up to date regarding IMpower133 and some more recent studies that use real-world data to talk about the 2 randomized phase 3 studies with patients with extensive-stage small cell lung cancer?

 Sure, I’m happy to. Thanks for the question. IMpower133 was the first major change to frontline treatment for extensive-stage small cell lung cancer in 30 or 40 years. Prior to that, going back to the 1980s and ’90s, it was chemotherapy alone with platinum-etoposide that offered reliably high response rates. But it also offered reliably high relapse rates, fairly short progression-free survival, and short overall survival. IMpower133 showed that adding the PD-L1 inhibitor atezolizumab concurrently with chemotherapy and as maintenance treatment to carboplatin-etoposide chemotherapy improved both progression-free survival and overall survival without adding notable toxicity.

This trial has a fairly straightforward design. Approximately 400 patients with previously untreated extensive-stage small cell lung cancer were randomized 1:1 to receive atezolizumab or placebo, given with 4 cycles of carboplatin-etoposide followed by maintenance therapy until progression or loss of benefit. We’ve recently updated these data. With longer follow-up, we see that benefit persists. We have a median overall survival of about 12.3 months with atezolizumab compared with 10.3 months in the standard arm. That has a hazard ratio of 0.76 and a 24% reduction of the risk of death. We saw an improvement in the 1-year survival rate of about 13%, from 39% to 52%. Interestingly, that was the exact same improvement at the 18-month survival rate. It’s reassuring to see that benefit persist with a little more follow-up. There’s a slight benefit in progression-free survival as well.

When we look at these curves, we see that they separate. It’s not the degree of benefit we are all waiting for, but it’s clearly an improvement over chemotherapy alone. We are trying to identify the patients who derive that benefit. The past few years, we’ve looked at various biomarkers, including tumor mutational burden and PD-L1 expression with various assays. It’s simply not useful in identifying patients who derive the benefit from atezolizumab. We see that benefit across the board.

More recently, we discussed the role of transcription subsets based on the expression of certain transcription regulators. Work led by doctors Charlie Rudin, Triparna Sen, and Lauren Byers was based on the expression of lineage-defining factors like ASCL1, NEUROD1, POU2F3, and the more recent inflamed subtype. Some subgroups, like the inflamed subgroups, seem to be enriched for atezolizumab benefit, but they simply aren’t useful in identifying who should and shouldn’t receive immunotherapy. Biomarker work is still ongoing.

At the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting, Dr Eric Nadler looked at some really weird outcomes in the US Oncology networks. IMpower133 was FDA approved in March 2019. The data were first presented in September 2018. This abstract looked at patients diagnosed with extensive-stage small cell between October 2018 and December 2019, with follow-up well into 2020. Of the 347 patients, 77% received atezolizumab, showing a very broad uptake of the regimen in practice. Of note, 55% of those patients were diagnosed as an inpatient, and 20% of patients received cycle 1 as an inpatient, which reflects most of our practices.

As you can imagine, this population was different from a clinical trial population. It was much older and more diverse, with more brain metastases—23% compared with 8% in the studies—and a worse ECOG Performance Status [PS], with 1 of 4 patients having a PS of 2 or greater. But the outcomes were similar. They were almost identical in terms of time on treatment, duration of therapy, continued therapy, and in marked survival. The real-world data based on this abstract matches up very closely to what we see in IMpower133, despite the population generally having worse prognostic factors.

Thank you, Stephen. You’re raising several important issues. I’m hoping we can come back to that when we have a general discussion. I love that real-world data because, as you pointed out, it’s a completely different patient population from what we get in clinical trials. We all realize that in the real world, that’s what we have. They’re very interesting data. It’s also very comforting and good to see that the results seem to match what we got in the clinical trial in terms of the clinical efficacy.

Stephen Liu, MD guides a discussion on recent updates on IO+chemotherapy combinations in extensive-stage small cell lung cancer by reviewing data from the phase 3 IMpower133 l trial of carboplatin/etoposide/atezolizumab. 


Hossein Borghaei, DO, MS, Fox Chase Cancer Center

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