® presentation, “Recent Advances in Small-Cell Lung Cancer.” We are going to spend the next 45 minutes focused on recent advances concerning both frontline and relapsed/refractory disease. I am your host, Dr Vivek Subbiah, a medical oncologist and clinical trials investigator from The University of Texas MD Anderson Cancer Center. Today, I am joined by my colleagues, who are experts in thoracic oncology: Dr Anne Chiang from the Yale University School of Medicine Smilow Cancer Hospital in New Haven, Connecticut; and Dr Apar Ganti from the University of Nebraska Medical Center in Omaha. Let’s get started.

Small-cell lung cancer (SCLC) is a highly aggressive, lethal, and widely metastatic lung cancer that kills an estimated 250,000 people worldwide yearly. This is based on the fact that small-cell lung cancer has an estimated 15% global lung cancer incidence and a 7% 5-year survival. Small-cell lung cancer is categorized by rapid tumor growth, high vascularity, genomic instability, early metastatic dissemination, and almost universal inactivation of 

 genes and frequent disruption of several characteristics signaling networks. Almost all patients with small-cell lung cancer are current or former heavy smokers. At this point, after decades of research, the prognosis for small-cell lung cancer patients remains poor, and treatment options are limited. Small-cell lung cancer is associated with more paraneoplastic syndromes than any other cancer type. To begin, let’s jump on frontline therapy for extensive-stage small-cell lung cancer.

Around 70% of patients with small-cell lung cancer present with extensive-stage disease on diagnosis. The remaining 30% of patients have limited-stage disease, in which the tumor involvement is confined to 1 hemithorax and can be treated in a tolerable radiation field. Let’s turn to an expert, Dr Apar Ganti from Nebraska. What has been the progress in identifying predictive biomarkers? Do you test for PD-L1 or tumor mutation burden (TMB) in small-cell lung cancer?

 Currently, there is no evidence to suggest that either PD-L1 levels or tumor mutation burden have a predictive role in small-cell lung cancer. Unlike non–small-cell lung cancer, where we know that increasing PD-L1 expression predicts increased response to checkpoint inhibitors, we do not have the same evidence yet in small-cell lung cancer. None of the recent frontline trials used either PD-L1 expression or tumor mutation burden as inclusion criteria, so the current standard of care is to not to check for either PD-L1 expression or tumor mutation burden in this cohort of patients.

 We know that small-cell lung cancer is an immunogenic tumor with high somatic mutation rates. This is mainly because these patients have tobacco exposure or a history of tobacco exposure resulting in potential new antigens, the presence of suppressed new responses, and the occurrence of paraneoplastic disorders. Dr Chiang, can you comment on PD-L1 and TMB in SCLC?

: As Dr Ganti said, PD-L1 expression is not predictive. It’s typically very low in small-cell, so that’s different from non–small-cell. There is 1 trial with pembrolizumab that looked at the combined positive score to take into consideration both the expression on tumor cells and immune cells. But on the whole, if you look at the regular assays that we use, small-cell is pretty much a negative tumor. There’s a lot of interest in TMB. It’s not standard of care, but the idea is that small-cell is a tumor. It’s within the top 10 tumor types. If you have a very high TMB and the presence of multiple antigens, there are more neoantigens that can boost the immune system response. Look at the original CheckMate 032 trial, which was presented at World Conference on Lung Cancer a couple of years ago. If you look at the response rate to immunotherapy, either nivolumab alone or nivolumab/ipilimumab, that was much higher in the TMB high—up to 46% response rate in that population. It’s a very intriguing marker. We’ll talk a little about that in the frontline trials that we’ll discuss, but so far, it hasn’t changed our standard of care to order those studies upfront on small-cell.

Introduction and Identifying Predictive Biomarkers

 Turning to Dr Ganti, can you comment on the recent progress in treatment of extensive-stage small-cell lung cancer with the availability of immunotherapy-chemotherapy combinations?

 Sure. Small-cell lung cancer, especially extensive stage, was in need of some advances in the treatment paradigm. For the last 25 years, we’ve been using platinum and etoposide as our backbone regimen. Until recently, there was no other treatment that was shown to be superior to this combination, and it was not for lack of trying. The first study that showed a benefit over standard platinum/etoposide was the IMpower133 study, which showed that adding atezolizumab, a checkpoint inhibitor, to platinum/etoposide increases overall survival. Since then, there have been at least 2 other trials. The CASPIAN study that showed that adding durvalumab to platinum/etoposide was better than platinum-etoposide alone. More recently as the ASCO (American Society of Clinical Oncology) annual meeting a couple of months ago, the addition of pembrolizumab to the same platinum/etoposide backbone regimen was associated with an improved progression-free survival (PFS) compared with platinum/etoposide alone. A smaller randomized phase 2 study looked at nivolumab/platinum/etoposide and showed an improvement in progression-free survival and improvement in overall survival with the addition of nivolumab. We have 4 trials with different checkpoint inhibitors that suggest that adding a checkpoint inhibitor to platinum/etoposide is better than chemotherapy alone. Of these 2 drugs, durvalumab and atezolizumab have FDA approval in this indication.

 Thank you so much. Do you have any comments, Dr Chiang?

 Sure. I think this is a very exciting time, as Dr. Ganti said, for small-cell. We’ve had several approvals in the past year and that, compared to 30 years of no approvals, so we’re very excited. The IMpower133 trial and CASPIAN trial have really defined the frontline standard of care. The IMpower133 trial showing OS (overall survival) of about 12.3 months versus 10.3 months and a hazard ratio of 0.76. The updated CASPIAN data just presented at ASCO showing 13 months versus 10.3 months overall survival with a hazard ratio of 0.73. It’s interesting. The point made on the CASPIAN trial is that the separation of curves at 2 years, that survival improved from 14% to 20% on the experimental arm versus control arm. That is that tail of the curve. It’s something we’re really excited about and looking for in this population, which clearly doesn’t have the median overall survival; it’s about a little over a year. We definitely need more research and ongoing investigation into to new therapeutic agents and options, but the addition of immunotherapy does help us have hope that there are some patients who can have really long-term survival.

For the CASPIAN trial, the combination of tremelimumab and durvalumab did not help, so adding that anti—CTLA4 antibody did not help. Just a word on KEYNOTE-604, which was the pembrolizumab trial: This was not statistically significant but certainly did have the overall survival and progression-free survival trends in the right direction. It looks very promising, but because of the way the study was conducted, it did not have statistical significance. The nivolumab/platinum/etoposide trial, ECOG-5161, was phase 2 but looked promising. The primary end point was PFS. The last thing I would add is that we have a couple of options upfront. How do you decide? It’s not absolutely clear that 1 is much better than the other, which is great. We have options for our patients. I think 1 of the differences in the CASPIAN trial was that it did allow asymptomatic brain metastases. If I have a patient who does have asymptomatic brain metastases, I might be more inclined to use that durvalumab regimen in combination with chemotherapy.

Recent Progress in the Treatment of SCLC

 Distilling from all these trials, what is your personal approach to treatment in a newly diagnosed patient that presents to your clinic? Let’s take it from Dr Ganti first.

 There are a lot of things to consider than starting patients on treatment. One of the important things I have encountered in practice from a logistics standpoint is a lot of these patients may have to start treatment in the hospital, and there are some logistical issues with getting the checkpoint inhibitors while the patient is in the hospital. Oftentimes we have to start them with platinum/etoposide, get the first cycle in the hospital, and then once they are in the outpatient setting, add the check point inhibitor afterward.

As far as deciding which check point inhibitor to use, the 1 striking thing I’ve found from the IMpower133 and CASPIAN studies is that even though there were some slight differences in the inclusion and exclusion criteria—as Dr Chiang mentioned, asymptomatic brain metastases were allowed in the CASPIAN study—it is striking how similar those results are, suggesting that this benefit with check point inhibitors is real benefit. Oftentimes you see when you have different studies that some show more benefit compared with the others, but if you look at all 4 of these trials that we’ve talked about and forget the statistical significance part of it, if you look at the magnitude of benefit—the difference in benefit, the absolute overall numbers—they are so strikingly similar to one another, suggesting that this is a real benefit. Based on that, I would suggest that all these patients be treated with a check point inhibitor in the first-line setting. My personal preference has to do with where I live and the distances people have to travel to come visit me. If you look at IMpower133, it was an every-3-week regimen, with the maintenance given every 3 weeks. The CASPIAN study was chemotherapy given every 3 weeks, with maintenance given every 4. I have had patients tell me that they would do whatever if they can make fewer trips. For patients who come to me from 3, 4 hours away, I tend to use durvalumab, whereas with patients who live close by and don’t have problems making the trip, either option would be fairly reasonable.

 Thank you so much, Dr Ganti. Let’s turn to Dr Chiang. Dr Chiang, which regimen are you using in your own patients, and does your clinical experience match with what was seen in the clinical trials that we just saw?

 Yeah. The fact that both IMpower133 and the CASPIAN trial showed very similar overall survival provides good options, validation No. 1, and good options for our patients. Both of them are good drugs. Within the non–small-cell space, we’ve had experience using both drugs. Atezolizumab is very well tolerated, and durvalumab we’ve used for consolidation for stage III non–small-cell, also well tolerated. I will say that with the COVID-19 (coronavirus disease 2019) in this era, we did look at converting our atezolizumab from every-3-week to every-4-week administration. For durvalumab, we also considered doing it every 6 weeks just to keep people out of the office and out of the health care system if we could. For patients with asymptomatic brain metastases, I would prefer durvalumab.

I agree with Dr Ganti that many of these patients are sick and started out in the hospital. We can’t start the immunotherapy in house, so we end up starting it afterward. Are they interchangeable? I don’t think we have information that says that 1 is clearly different from the other. Aside from the brain metastases issue, we could probably use either 1. I have used both. Additionally, we used the atezolizumab that had FDA approval sooner, but now I have been using durvalumab as well. I would just mention that 1 issue that constantly comes up in our tumor board is if the patient has persistent disease, do you consider thoracic consolidation? A fight we have every week is between the radiation oncologists and the medical oncologists. The radiation oncologists say, “Gee, it’s certainly tolerated well with immuno-oncology and the radiation, and we think we can have a better benefit.” But clearly, the trials did not include thoracic consolidation, so if you’re a purist, you really try to follow the data. For me, unless there’s a clear reason to use radiation—for example, if the patient is symptomatic and there is a need for some local effect—then I hold off on that, but I know that’s a bone of contention. I don’t know what you guys do.

 I agree. That has been a challenge. What I tend to do is, if someone has had good response outside the chest and has a less severe disease within the chest—of course, we don’t know if this is inflammation with that tumor tissue—I at least talk to the patient about possibly considering thoracic radiation. I understand that neither of the trials allowed it, so it is a data-free zone if you will, but given what we know about the benefits of thoracic radiation and the kinds of people it will benefit, I would tend to offer that small portion of patients thoracic radiation. If I see a good response in the thorax, more than 90% shrinkage and good disease response outside the chest, then I’m not so sure those individuals necessarily need added radiation to the immunotherapy. I agree that we’ve done radiation with immunotherapy in multiple other diseases, and the combination seems to be well tolerated. We’ve not had too many adverse effects in that setting, so I don’t have any problems with that, but given that these trials did not include them, I would not offer it in everyone, just a select portion of patients for whom I think adding the radiation would help improve the quality of their response.

Personal Approach in Treatment Compared to Clinical Trials

 One more question I have now is, what tactical advice would you share about the expected toxicity management, especially if you want to combine them with radiation all in the COVID-19 (coronavirus disease 2019) era?

 One of the things that becomes difficult in the COVID-19 era is if you see pulmonary infiltrates, you don’t know what they are. Of course, it’s important not just to trust your scans but also talk to the patient, see what other kinds of symptoms that they are having. My approach has been that if they have not had other classic symptoms of an infection, like fever, then I would not necessarily blame it on COVID-19, but rather consider this immune-related pneumonitis. I would have an intermediate threshold for stopping the immunotherapy because, yes, it is very beneficial, but at the same time, you don’t want pneumonitis to get out of hand. I would monitor them closely, check their symptoms, monitor that; this becomes even more important in the setting of those patients we give thoracic radiation to. You have to be very clinically alert in distinguishing between the pneumonitis due to checkpoint inhibitors due to radiation if you offer them thoracic radiation. With COVID-19, I’m not aware of any CT scan findings that would differentiate 1 from the other, except that radiation pneumonitis is within the radiation field, and if you see something outside, you have to worry about other things. That is 1 practical aspect.

The other things is, we’ve been taught that we have to use steroids for immune checkpoint inhibitor–induced toxicity. At the same time we have to be a little concerned about the possibility of higher doses of steroids affecting the response rate to the treatments. That’s a fine balance. What I tend to do is if I have a patient who is overtly symptomatic, then I would stop the checkpoint inhibitor and start them on steroids and try to ween them off steroids as quickly as possible. Of course, we need to understand that some of these patients need a much longer taper and then hold them off. Whether to rechallenge with the immunotherapy drug depends on how severe their initial symptoms were and how quickly they respond to steroids. So those are some of the practical tips I’ve learned while using these drugs in this particular setting, especially in the COVID-19 era.

 Perfect. Thank you, Dr Ganti. Do you have anything else to add, Dr Chiang?

 These drugs are very well tolerated. The grade 3, 4 in the studies, adverse events were really in the 2% to 5% range with rash, hepatitis, and colitis the main things that people were worried about. Obviously, we do worry about pneumonitis. In the COVID-19 era, we see some of our patients with telehealth. Just to follow what Dr Ganti said, these are patients probably who would be better not being seen by telehealth but in person, so you can really evaluate their oxygen saturation and their vitals, listen to their lungs, and see how they’re doing. With regard to the steroids, many of our protocols allow patients who are on prednisone of 10 mg or the equivalent, or below, to be on trial getting checkpoint inhibitors. There have been data within that realm to show that that seems to be okay. Rechallenge is possible, although I think you really have to be careful. Hepatitis is not something that we generally rechallenge for.

Advice on Toxicity Management for SCLC Therapy

 Thank you, Dr Chiang and Dr Ganti for sharing your perspectives on front-line management of small-cell lung cancer. Now that we’ve discussed frontline therapy, the next topic is the most challenging one in the clinic and for research, which is the relapse/refractory small-cell lung cancer. Dr Chiang, would you use an immunotherapy (I/O) regimen after progression chemo or chemo-I/O combination?

 I do have an investigator-initiated trial looking at IPI/NIVO (ipilimumab/nivolumab) for relapse disease with the idea of utilizing an anti–CTLA-4 and anti–PD-1 combination to salvage patients who progressed on ATEZO (atezolizumab). Obviously, the CASPIAN data with DURVA (durvalumab) and TREME (tremelimumab) was negative, but we’ve also seen in other instances that the DURVA/TREME combination may not be so active and mystic. I do think that IPI/NIVO has had a good track record in CheckMate-032 for small-cell, and this particular trial is really looking at biopsies and pretreatment to look at whether the ratio of CD8 to FOXP3 cells—the ratio of effector to T regulatory cells—can correlate with response, with the clinical question being can you use a combination to salvage progression on 1 single agent? I’ll comment in terms of looking at mechanisms of acquired resistance in non–small-cell. There are data in colorectal tumors that impaired antigen presentation, MHC (major histocompatibility complex), or beta-2 microglobulin defects that can be a mechanism. That’s something we’re interested in looking at because we know that, unfortunately, while we’re looking at the tail of the curve, the current data show that almost all these patients will progress and require second-line therapy if they have the performance status. There’s a possibility that we can salvage with combination I/O. Certainly, if we learn from the non–small-cell, if you use combination chemo-I/O upfront, then you usually go to a chemo regimen. I think we have some exciting new chemo options, at least one that we’ll talk about today, and then we may need to recycle some things so our patients who have good performance status can still continue with treatment.

One more question I had for you is, would you think about re-challenging with platinum and etoposide combination for the second-line?

 For small-cell, we do have literature talking about platinum-sensitive disease, which is typically if you are strictly looking at 6 months, although a lot of trials look at recurrence within making it through the 3-month range. I do think that is an approach that we’ve used with pre-immunotherapy. We don’t know how it looks for patients on maintenance ATEZO or maintenance DURVA. I think we would probably add back the platinum if it’s been a long time, for example, 3 or 6 months, but this is a bit of a data-free zone because we didn’t have the IO when we were looking at the platinum-sensitivity before.

 Do you have any insights to share on second-line therapy for small-cell, Dr Ganti?

 I have a slightly different take than Dr Chiang about re-challenging with immunotherapy. If you look at CheckMate-032 in the relapse setting, the addition of ipilimumab and the nivolumab added the increased response rate but did not necessarily increase the duration of response of survival. In that setting, adding IPI in someone who’s progressing while on maintenance DURVA or ATEZO… I’m not sure that I would necessarily use that. I would use a different agent in that setting. As far as re-challenging with platinum/etoposide is concerned, I agree with Dr Chiang that if it is for more than 6 months, and sometimes even more than 3 months, since the last dose of these agents, I would tend to re-challenge with them. If someone is on maintenance immunotherapy when they progress, I would use their duration from the last chemotherapy cycle to decide whether or not to re-challenge with platinum/etoposide. If I decide to use platinum and etoposide, I would not necessarily continue with checkpoint inhibitor; I would use chemotherapy alone. Again, there is very little evidence one way or the other because, like Dr Chiang said, the data on re-challenging with platinum/etoposide was done in an era when we did not have immunotherapy, and those patients were not on any treatment when they relapsed and were re-challenged with platinum/etoposide.

 I just want to make sure that I had responded about IPI/NIVO. That’s within the context of a clinical trial. Off-trial, I would not give IPI to those patients. I would move on to chemotherapy, and I think that the classes of chemotherapy that are effective in relapse small-cell are… Topotecan was previously the only FDA-approved therapy. There are a lot of people who don’t like topotecan and don’t think it’s effective, but it is an option for the patient to go on an oral therapy and take a break from IV therapy. I think taxanes are very active for small-cell. Temozolomide is also a good option, especially if you are worried about progression or disease in the brain. There are approaches with maintenance strategies combining I/O with PARP inhibitors that are now available in clinical trials, so I think there are different options for these patients if they have the performance status. I will say, just anecdotally, I had a patient who came off of maintenance atezolizumab, went onto my IPI/NIVO trial, and then subsequently went on topotecan and had an extended response to topotecan, over 8 months. I don’t know what these checkpoint inhibitors are doing to sensitize the body to boost them when you have chemotherapy and cytotoxic chemotherapy subsequently. I think postprogression chemo added to or after immunotherapy is very interesting.

Use of I/O Regimen in Relapsed/Refractory SCLC

Small-cell lung cancer in the relapse/refractory setting still is an aggressive cell malignancy. Uniformly, almost all patients relapsed. So far, we’ve had topotecan as the only FDA-approved agent in the past 2 decades in second-line small-cell lung cancer, platinum-sensitive disease. Again, the challenge, as you mentioned, with topotecan is due to its modest clinical benefit; the objective response from various clinical trials range anywhere from 5% to 24%, and median overall survival from other topotecan studies that we could see is 6 to 8 months. In these patients who have shorter overall survival, they show some significant hematologic toxicity as well. We needed different drugs in our armamentarium, especially in the second-line setting and that are non–immuno-oncology (I/O).

Recently, several new agents failed to demonstrate benefit in the second-line setting. Enter, lurbinectedin. Lurbinectedin is a selective inhibitor of oncogenic transcription. By inhibiting active transcription in the tumor-associated macrophages, lurbinectedin downregulates IL-6, IL-8, CCL2, and begets. As we all know, a small-cell lung cancer is transcription-addicted tumor. Recently, 4 molecular small-cell lung cancer subtypes have been defined by differential expression of 4 key transcription regulators. Initial lurbinectedin antigen tumor activity in small-cell lung cancer was observed in phase 1 to 2 study in combination with anthracycline/doxorubicin. Interestingly, that trial showed an objective response rate of 37% and a duration of response of 5.2 months.

Most recently, lurbinectedin was FDA approved. This approval was based on a multicohort basket study. Efficacy was demonstrated in a PharmaMar-led basket study, which is a multicenter, open-label, multicohort study, with only 105 patients with metastatic small-cell lung cancer who had disease progression on or after platinum-based chemotherapy. I was one of the co-investigators for this clinical trial for this multiarm clinical trial that enrolled not only small-cell lung cancer patients but also aggressive tumor types like Ewing sarcoma and germ cell tumors. Again, this specific small-cell lung cohort enrolled 105 patients with metastatic SCLC (small-cell lung cancer) vibrations with metastatic small-cell lung cancer. Patients received 3.2 mg/m2 of lurbinectedin by intravenous infusion every 21 days until disease progression of unacceptable toxicity. The main outcome measures were confirmed overall response rate as determined by the investigative assessment using the RECIST version 1.1 and response duration. Among the 105 patients enrolled, the objective response rate was 35%, with a median response duration of 5.3 months. The objective response rate for independent review committee was 30%, with the median response duration of 5.1 months. The most common adverse event that we saw more than 20% of the time in these patients enrolled on the clinical trial was myelosuppression. This is a chemotherapy, and the most common adverse effects were myelosuppression, fatigue, and some patients had elevated creatinine. We need to be cognizant that these patients have all come from cisplatin-, platinum-, and etoposide-based therapy. They have borderline renal function, including some liver function abnormalities and this glucose, nausea, decreased appetite… Vomiting and cough were also seen together with diarrhea.

The recommended phase 2 dose for the FDA label was 3.2 mg/m2 every 21 days. It received an accelerated FDA approval. The benefit observed with lurbinectedin compares favorably with what we historically see with topotecan. This is a current standard of care in terms of both anti-tumor activity and safety. Lurbinectedin is FDA approved, and it was also added to the NCCN (National Comprehensive Cancer Network) guidelines on June 7, 2020.

Let’s talk to Dr Ganti and Dr Chiang on how they think the approval will impact the treatment armamentarium in small-cell lung cancer. First, Dr Ganti.

 Lurbinectedin is the first drug that has been approved in this setting for a long time, and we are all excited about it. We finally have some alternative to topotecan. As Dr Chiang mentioned earlier, topotecan was available, but no one really liked it because of the myelosuppression and the toxicity associated with it. As you mentioned earlier, the outcomes were not great. Response rates ranged between 10% and 25%, with a median overall survival between 6 and 8 months. There was a big need to improve upon that. Lurbinectedin seems to have done that, at lease in some measure. As far as my practice is concerned, I will be using more of this drug in this cohort of patients. From the phase 2 basket trial that you just described, it appears that the adverse effect profile was very manageable. Myelosuppression was not as significant compared with topotecan, with the understanding that these 2 drugs have not been compared head-to-head in a clinical trial. There is an ongoing phase 3 trial comparing the combination of lurbinectedin and doxorubicin with topotecan, and that will give us more details and a better idea of what the exact benefit of lurbinectedin is. Based on this phase 2 data, I think that this would be a useful addition to our armamentarium in regard to small-cell lung cancer.

 Do you have any other insight into this drug, Dr Chiang?

 I think this is a great option for our patients. We have this epic treatment plan built, we’ve been pushing to get this drug into patients, and it’s actually available. I just got an email this week. We’re very excited. I think that patients are excited. It’s well tolerated, and 35% overall response rate is much better than what we’ve seen with our standard agents. I think this is a great option.

Data on FDA Approved Therapy for Relapsed/Refractory SCLC

 In the clinic, if a patient walks in who has progression from frontline treatment and you have lurbinectedin available, would you use lurbinectedin over any other agent in the absence of a clinical trial?

 I would. As I said, the biggest adverse effect with topotecan has been myelosuppression and the ability to give it on a scheduled basis; you dose reduce to decrease the amount of myelosuppression. Based on what we know with lurbinectedin, I think that has a much better toxicity profile, and its myelosuppression seems to be lower than topotecan, so I would definitely use that.

 I agree. For these patients who have disease that’s not going to be cured, we’re looking for the ability to maintain their quality of life and use a number of different tools. This is something that’s well tolerated. It has a good response rate. The interesting thing will be for the patients who have platinum-resistance versus -sensitive disease. The 45% response rate for those patients who’ve had platinum-sensitive disease may point to this being an option prior to using platinum again. That’s something that remains to be seen, and it certainly depends on how the patients are doing. We need to get a little experience with this drug in the clinics.

 This is a very important point that you bring up about what you do in platinum-sensitive patients. We didn’t have any great options, so we used platinum again. Now we have another option that appears to be as good, this is something that we could potentially use. Having said that, I think there is still a role for rechallenging with platinum. We don’t have too many great options. If I have someone who has had 6, 7 months since their last dose of platinum and has a good performance status, I might challenge them with platinum/etoposide again because I know that I can use this drug later on when they relapse at some point, and the disease-free interval after the second platinum is less than with the first time they get it. With the sequencing of drugs, if they have a better performance status, they may be able to tolerate platinum/etoposide. If we give them lurbinectedin first and their performance status worsens when they progress, they may not be able to tolerate platinum/etoposide and will have to find some other drug at that time. That is a subtle nuance I might consider in treating those specific individuals.

 In the context of immunotherapy and lurbinectedin, when this lurbinectedin trial was designed, I don’t think immunotherapy was the standard of care. It was mainly available in clinical trials. Going through the clinical study, 2 patients (8%) had received prior immunotherapy as first line and 6 patients at second line as treatment. In a post-hoc exploratory analysis of this small group of patients, 5 of these 8 patients (63%) had agreeable responses to lurbinectedin, according to investigator assessment. Immunotherapy and lurbinectedin have different mechanisms of actions. When we combine immunotherapy patients who progressed from frontline immunotherapy or second-line immunotherapy, they could be candidates for lurbinectedin. We are waiting for further data on this, but having another drug in this area is a major boost in the clinic for patients.

 What you just said makes a lot of sense in the context of what we discussed earlier about responses to post-immunotherapy chemotherapy. As Dr Chiang said, evidence of great response to topotecan after someone had progressed on checkpoint inhibitors seems to be similar to what we found post-hoc in the lurbinectedin study. There may be some signal there about how previous immunotherapy may prime responses to subsequent cytotoxic chemotherapy. I think that would be a good topic for further investigation going forward since there are only a limited number of options for these patients, and we need to be trying to find creative ways of treating them.

 In summary, I think lurbinectedin appears to be a valuable treatment option and addition to our treatment armamentarium. The benefit of lurbinectedin compares favorably with that seen historically with topotecan and many of the new agents that have been recently tested in clinical trials in terms of both antitumor activity and safety.

Role of Newer Agents in the Treatment & Patient Selection

 What other unmet needs and challenges are there in treating relapsed/refractory small cell lung cancer? Dr Ganti?

 We talked about new options like lurbinectedin and immunotherapy, but at the end of the day, overall survival in the relapsed setting, even with the phase 2 data from lurbinectedin, is still less than a year old. Earlier, we talked about immunotherapy being a big advance; again, the median overall survival is only about 13 months, slightly more than a year. We need better drugs, and we have to do better in this disease. There is a big unmet need, the recent advances in the use of immunotherapy notwithstanding. We need to do better by our patients. I think there is a lot of effort that needs to be put into identifying newer drugs and newer pathways, understanding the mechanism of resistance, and looking at biomarkers to see which patients can benefit and which don’t so we don’t expose them to some of these adverse effects. Those things need to be looked into for small cell lung cancer.

 Clinically, I think that brain metastases are a difficult challenge for these patients. Many of these patients have metastases to the brain, either at diagnosis or during the course of their disease; once they’ve had prophylactic cranial radiation or whole-brain radiation, you often see situations where you have progression or recurrence in other parts of the brain, and they’ve maxed out on radiation therapy. You certainly can use Gamma Knife [radiosurgery] or local approaches. Then there are some drugs that have penetration through the blood-brain barrier, such as temozolomide and some of our standard drugs like taxanes or topotecan as well. For this population, brain metastases are difficult. Many of the clinical trials will also exclude patients who have a history of brain metastases. Sometimes we have patients with leptomeningeal disease.

I think that, as Dr Ganti mentioned, understanding the biomarkers that can predict response is important. This is a heterogeneous population of patients and, Dr Subbiah, you already referred to a new paradigm in thinking about this disease, that there are ways to categorize molecular subtypes that overexpress certain genes, such as 

, or other ones. Those different subtypes can also have a different natural history of the disease. I think that being able to dissect what kinds of small cell lung cancer they have and then figure out more targeted approaches for those subtypes would be great and will continue to be one avenue of investigation. Biomarkers such as TMB [tumor mutational burden] look at the tumor microenvironment and infiltrate T cells. There may be a blood-based analysis of the circulating tumor DNA or other assays that are not based on obtaining tissue but on the blood that can be very useful in managing this disease. I think tissue is something that’s difficult for these patients. Many of them are still diagnosed via fine-needle aspirates, and I think that the more tissue we can get to study, the more useful it will be to help figure out what’s going on. Ultimately, thinking about the patient as a whole and how they’re resilient and respond to this disease is super important. Many of these patients have a terrific response to chemotherapy, in the 60% to 80% or sometimes even 90% response range, and they’re blindsided. Even though you tell them at the beginning, they’re blindsided when they have recurrent disease and have to shift their paradigm to thinking about different ways of coping and the impact of this disease on their lives. I think there still needs to be a lot of work in that area to investigate how patients can develop approaches to be resilient and cope with an incurable, chronic disease. We hope that the tail of the curve pans out for these patients, that some of those treated with immunotherapy can have an extended survival. I’ve had patients who have done very well. There’s a lot of room for hope.

 I think in small cell lung cancer, especially in relapsed/refractory disease, we have miles to go before we sleep. We are hopeful that, given the enthusiasm with multiple agents being approved in small cell lung cancer and in clinical development, there is more enthusiasm in this field.

Unmet Needs and Challenges in Treating R/R SCLC

 Before we end this discussion, we’d like to incorporate some of the questions submitted in advance by our viewing audience. I think we’ve touched upon several of these during the course of our discussion, but let’s take one at a time.

Is there a role for NGS [next-generation sequencing] testing in small cell lung cancer, given that 

, TMB [tumor mutational burden], and MSI [microsatellite instability] have a histology-agnostic approval for agents and more physicians are going to be testing for a broad-based panel? Is there a role for NGS testing in small cell lung cancer? Dr Chiang?

 I would love to do NGS testing on all of these patients, but it’s not covered, at least not upfront. I do think, upon progression, it is something that I try to do with these patients. I try to get information, a biopsy if it is appropriate, often on a clinical trial, to try to understand more if there are other therapeutic options for these patients. Many of them, as you mentioned at the beginning, will have 

 mutations that we don’t have a target for, but if there are other targetable mutations, that’s part of creating more tools to combat the disease for individual patients.

 Dr Ganti, we spoke about lurbinectedin. This seems like a new drug that will be an added value to our treatment. What would potential combination therapies with lurbinectedin look like? Do you think it can be combined with other agents?

 I think so. If you look at the mechanism of action of lurbinectedin and the safety profile, it is fairly safe. You could potentially combine it with either other cytotoxics or with immunotherapy because we know that, at least in the non–small cell lung cancer setting, chemotherapy plus immunotherapy seems to have a better response rate than immunotherapy alone. That is an approach that we could borrow from that disease paradigm to use in the relapsed setting. If you could understand the mechanisms of resistance for lurbinectedin, we could potentially combine it with drugs that would work on providing disease control and progression-free survival. Those are definitely options that I would consider right now. As we understand more about the biology of small cell lung cancer, I’m hoping we’ll find new pathways and try to identify ones where they would be synergistic with lurbinectedin and use that in combination. There is potential for combining it because it seems to be a relatively well-tolerated drug.

 Dr Ganti, Dr Chiang, thank you. Small cell lung cancer remains a challenging disease in need of new therapeutic opportunities. Lurbinectedin appears to be a new, valuable treatment option. Activity of lurbinectedin in combination with doxorubicin for second-line in small cell lung cancer therapy is being investigated in a randomized phase 3 trial, ATLANTIS. We also saw that the use of immunotherapy can benefit patients with small cell lung cancer by generating effective antitumor responses in the host. Considering this disease is an immunogenic tumor with highly somatic mutation breaks, it also displays a very immunosuppressive phenotype that hinders the therapeutic advances in immunotherapy. This may biologically explain, in part, the recent conflicting results of the efficacy of various immune checkpoint inhibitors in small cell lung cancer. The results of ongoing large, randomized studies, including the one for lurbinectedin with doxorubicin—along with future research and novel immunotherapeutics, as well as newer combinations—are expected to define the final role of immunotherapy and all other agents in the treatment algorithm for small cell lung cancer.

This has been an excellent discussion, and thank you for your participation. To our viewing audience, we hope that you found this information to be valuable to your clinical practice. Thank you all for watching this 

Recent Advances in Small-Cell Lung Cancer | News Network