It’s been great updating our viewers on the new options or emerging options for mesothelioma. As we wrap up this program, I wanted to give our panel a chance to have their parting thoughts. Maybe we can ask them what they’re most excited about looking to the future, about non–small cell lung cancer and I/O [immuno-oncology] therapy.

 I’m excited about the combination treatments and to see some research going on for patients who failed first-line PD-1 or PD-L1 inhibitors. I would like to see some more biomarker studies. I’d like to see some data that once you reuse a single agent vs dual immune checkpoint inhibitors, once you redo the combination of chemotherapy plus immunotherapy, immunotherapy plus anti-VEGF treatment. It means very little to my patients. I tell them the future looks bright. They really care about what’s available today in our clinic, and we have a lot of options for them. Despite all this excitement about the future research, I’m very happy where we stand today for our patients.

I second that. There are a lot of positive developments. I’m most excited because some of what has already been coming through at this ESMO [European Society for Medical Oncology Congress] meeting is the combination of targeted inhibitors in the right setting with the addition of immunotherapies. We’ll have to get used to the fact that certain kinds of cancers are driven by oncogenes and change our paradigm, that they may be still immunotherapy responsive, 

 probably being the prototypes. There have been some data in other disease spaces, where there seems to be a feasible option, even in the combination setting. We’re always concerned about TKIs [tyrosine kinase inhibitors] plus immunotherapy, but this may just be the wrong disease background, maybe even the wrong TKI where we’ve observed these findings. This is going to be very exciting.

The other part is if I look into the future and look at the new developments, people have to get used to the fact that there’s not going to be a unifying epitope, and that combinations, doublets, or even triplets will become a very reasonable alternative. It’s going to be important for us to build up multidisciplinary support systems for immunotherapy agents, where we can manage these adverse effects comprehensively early on with a lot of skill and expertise, and we can extend that benefit of multiagent immunotherapy to as large a patient population as possible.

Of all the studies we talked about today, PIONeeR is the 1 I’m most excited about. This trial is going to give us a significant number of patient tissue samples for us to ask all the important biomarker questions and to hopefully gain some insight into which patients are going to be responders, who is going to develop resistance, and what is the mechanism of that resistance, so we can potentially tackle it further down the line.

 The most important studies are some of the data that you presented on CheckMate 227, that Julie Brahmer presented on KEYNOTE-024, that long-term follow-up, because we are seeing that these improvements in survival are leading to impressive long-term landmark survival rates and, I would say, curing a significant portion of our patients. As we look to the future, delivering that to surgical patients where outcomes really are quite poor, and the neoadjuvant setting is going to bring that benefit even more pronounced.

 Thank you. And for my part, I would echo some of the comments that have been made. What I’m most excited about is that we’re beginning to learn more about individual patient characteristics that provide responses to immune checkpoint inhibition. We’ve barely scratched the surface, but that knowledge is increasing, and that information is going to help us personalize immunotherapy for patients the way we’ve personalized targeted therapy for a subset of non–small cell lung cancers.

It’s been a great discussion. I’ve enjoyed learning from all of you today. I hope our audience finds this program informative and helpful to their patient care. I want to thank Dr Badin, Dr Dietrich, Dr Bestvina, and Dr Liu for participating in this panel. Thank you again to our audience for joining us. We hope you found this 

® discussion useful and informative. Thank you.

Videos

The Future of Lung Cancer Treatment

 When we think about mesothelioma, 1 of the early observations was how high the patient’s VEGF circulating levels are and that led to the evaluation of bevacizumab-based regimens. Martin mentioned the MAPS study. Steve, where does bevacizumab fit in the mesothelioma-treatment landscape?

 Until CheckMate743 at World Lung [World Conference on Lung Cancer 2020], this was my standard of care. I admit that it was not FDA approved, though it is approved in other parts of the world. The addition of bevacizumab improved survival. It’s very tolerable, and I continue that as maintenance. Until recently, that was my preferred standard of care, with a modest but real improvement in outcomes. But I agree with my colleagues: We’ve been looking for much better. CheckMate743 offers another option, another line of therapy, and while the outcomes were best in the PD-L1 positive, they were best in the nonepithelioid subsets, which were, by the way, the subsets with the worst prognosis overall. Even in patients who were PD-L1 negative or in the epithelioid, this becomes my preferred option. It allows me to move platinum-pembrolizumab-bevacizumab to second line for patients who don’t get that response. I’m a little nervous about when people don’t respond. Are they going to become increasingly symptomatic?

There are a lot of parallels between mesothelioma and non–small cell lung cancer. We’ve got a dual checkpoint blockade strategy, which seems to be very effective, in certain subsets clearly better, in others comparable, and you have to wonder if there’s a role to combine strategies.

 Talking about parallels between non–small cell lung cancer, as we think about ipilimumab-nivolumab it’s hard not to think about chemotherapy plus I/O [immuno-oncology] strategies in mesothelioma. Steve, we have 2 studies. Why don’t you talk about the DREAM3R study that was recently published.

 The DREAM3R trial was an Australian study led by Anna Novak, looking at patients with mesothelioma, with a combination of durvalumab with cisplatin-pemetrexed. What we saw was the outcomes in that study were quite impressive. It’s difficult to know, though, how much durvalumab was adding really as opposed to just the passage of time. When we compared the initial EMPHASIS trial with the MAPS study, that even those same arms of platinum-pemetrexed improved over time because of better supportive care and better lines of therapy. In a single-arm phase 2, there’s only so much you can learn, but still the outcomes in DREAM3R with durvalumab and chemotherapy were quite impressive, with the majority of patients, almost 60%, still alive and progression-free at 6 months. That’s certainly a clear signal that we need to build on.

 I would also add that the PrECOG study, which also looked at the same approach—chemotherapy plus durvalumab for first-line treatment of mesothelioma—was reported at ASCO [American Society of Clinical Oncology Annual Meeting] by Dr Patrick Forde, and the results were very impressive. The median survival was upward of 20 months for this group of patients. When we specifically looked epithelioid type of patients, the median survival was even better in that subgroup. Patrick also showed some biomarker work in this patient population that’s early, that needs to be developed further. But certainly it gives some insights that could potentially lead to benefit for this chemotherapy-immunotherapy approach. The good news is there is a follow-up study planned that hopefully will launch very soon. This will be a phase 3 trial of chemotherapy plus durvalumab compared with chemotherapy alone, and it will be done globally in collaboration between PrECOG and the Australasian Lung Cancer Trials group. Hopefully that trial will help us answer this question in mesothelioma. A lot of excitement with the integration of immunotherapy in mesothelioma, with ipilimumab-nivolumab now becoming an option. Hopefully it will get approved soon so we can use it in our clinics.

One continuing question is what happens when patients progress on first-line therapy? If they get chemotherapy, what is your go-to regimen? I want to hear briefly from our panel on that.

 There are not a lot of great options, right? We look at the comparators with the pembrolizumab data. The standard chemotherapy is vinorelbine or gemcitabine, and those are our standards now with very modest outcomes and a low ceiling for both regimens. I use vinorelbine in those settings, but this is a case in which you need to find a trial. If 1 is not nearby, then you need to refer to a specialty center, because the standard treatments are not very good.

 I agree completely. I don’t think we have great options or we have a standard of care for those patients. A lot of us believe mesothelioma is a surgical disease. I’m interested in neoadjuvant approaches. I’d like to see maybe adopting some immunotherapy in the neoadjuvant setting with chemotherapy, hoping that we can resect more patients and maybe cure more patients. In subsequent lines of treatments, I don’t have great success. You can try different kinds of single-agent chemotherapy agents, but really it doesn’t add much.

 Thank you. Does anyone consider reintroducing platinum-pemetrexed if the patients did well in the frontline setting? I’ve done that for a couple of patients, and at least you get stable disease out of it for a few months and results in some improvement in their overall quality of life.

 There’s some activity there. You notice we don’t talk a lot about reintroducing platinum or revisiting those doublets in non–small cell, because we have better options. The fact that we’re revisiting those older treatments in mesothelioma and small-cell lung cancer reflects the lack of other better alternatives. But I’ve been in similar situations, and if patients had good tolerability, good outcomes, and it’s been a little while, then I’ll absolutely revisit those just for lack of anything better.

Mesothelioma: A Look at DREAM3R and PrECOG Trial

 Mesothelioma is a rare disease, but certainly we see enough of them in our clinical practice, and it is important for us to have a conversation about some recent developments that will guide management. Christine, at your institution, you have a long track record of developing novel approaches to treat mesothelioma. Tell us about the standard of care and how we got here.

The real staple of treatment for mesothelioma has been cisplatin. We built off of cisplatin with a trial back in 2003, which added pemetrexed to cisplatin in a randomized fashion and did demonstrate an improvement of overall survival at that time of 9 to 12 months with the addition of pemetrexed. We continued to try to build on this combination therapy and finally, with the MAPS study, the addition of bevacizumab demonstrated an addition of 3 months of overall survival.

However, for these patients it was still disappointing based off what histology the patients had. There are 2 main buckets of mesothelioma patients, the epithelioid and the nonepithelioid patients, and we’ve just struggled to have any great treatment options for these nonepithelioid patients, and it seems to have to do with chemotherapy resistance.

 Thank you. When mesothelioma is diagnosed, the first question always is, is this surgically resectable or not? Steve, what are some things that would help make that determination?

 That’s something we need to discuss with an experienced surgical team. Fortunately, I sit down with my surgeons and go through things. We’ve moved a bit away from more radical surgeries, like extrapleural pneumonectomy, and look more at localized, pleural-stripping surgeries. There are some who think that mesothelioma is not a curable disease, even those who present who are surgical candidates. I would agree that relapse rates are very high. Avoiding very morbid procedures is appropriate. This is a cancer where regardless of stage, systemic treatment is important.

 Thank you. When we have a patient with mesothelioma, Christine mentioned the median survival with systemic chemotherapy at this time is about 12 to 13 months. We’ve also seen qualitative improvements in those studies where a patient’s respiratory function improves with systemic chemotherapy. Is there a role for maintenance pemetrexed? You’ve given patients 6 cycles of cisplatin-pemetrexed. A recent study suggested perhaps not so. How do you approach that situation, Martin? You get the 6 cycles of chemotherapy, then what’s your next step with these patients?

 Fortunately, we don’t have that many of them to say that. This is a segment of the country where mesothelioma is not as common, but we have a lot of patients from New York with asbestosis preload who are developing mesothelioma. We typically do not consider the addition of maintenance therapy, partly because of the toxicity, the cumulative toxicity of cisplatin. We see declining kidney function as a concern, also for the maintenance dosing of pemetrexed. I’m not 100% certain about the addition of bevacizumab. There seems to be some improvement in the MAPS study, but it’s not FDA approved, so it’s a little more challenging. It’s in the NCCN [National Comprehensive Cancer Network] Guidelines but not necessarily as the defined standard of care, and this is reflected in this treatment.

It’s a very difficult-to-treat disease. There is no early intervention. There’s no real surgery, which makes this ESMO [European Society for Medical Oncology Congress] presentation of the introduction of immunotherapy in the first-line setting so interesting. We’ve seen the CheckMate743 trial as a phase 3 randomized trial comparing cisplatin-pemetrexed against the combination of ipilimumab-nivolumab, in the same dosing regimen like we’ve seen in CheckMate 227 with nivolumab every 2 weeks and ipilimumab given every 6 weeks at the low dose of 1 mg/kg body weight. They were interesting to be separated into epithelioid and nonepithelioid subtypes, and there clearly seemed to be a preferential effect in what we thought to be the more challenging-to-treat subtype, which was the nonepithelioid type, and a very equivalent performance of ipilimumab-nivolumab in the epithelioid subtype.

With regard to expectations for mesothelioma, it’s surprising. Most of the single-agent immunotherapy trials have either been abandoned or reported out negative. It’s interesting to see that we have responses here with ipilimumab in the first-line setting, particularly in the PD-L1–positive subset of patients. PD-L1 may be a prognostic marker to be looked at, to guide a discussion; maybe not to select treatment but to guide a discussion. In my opinion, this is a practice-changing part for sure against cisplatin-pemetrexed in the nonepithelioid type, but I don’t have a good reason in the absence of referential considerations with comorbidities to not use it as a standard of care in the epithelioid subtype either. The efficacy and outcome are the same. The adverse effects are typically milder than cisplatin-pemetrexed, and there is a population of long-term responders. We don’t know why they occur, but they certainly do, and it’s something we really don’t see much in the chemotherapy-treated arm.

: Firas, how much of that enthusiasm do you share for the ipilimumab-nivolumab regimen in mesothelioma?

 I agree with Martin. This practice is changing to have a chemotherapy-free regimen in such aggressive disease, difficult disease to treat, with such a big survival advantage with nivolumab-ipilimumab. Here is another time where this combination, PD-1 plus anti-CTLA4 combination, showing survival advantage regardless of different histology of this disease and regardless of PD-L1 status. That’s exciting, especially if you have somebody with nonepithelioid histology where chemotherapy historically does very poorly, this is a wonderful option. In the epithelioid histology, where you’re trying to avoid chemotherapy in somebody who is older, this is also a wonderful option. I wonder if we can adopt the 9LA approach with 2 cycles of maybe cisplatin–Alimta [pemetrexed], plus nivolumab, plus ipilimumab, and then you go to maintenance. I would also love to see something like that come into this disease. It’s not a common disease. I don’t see a lot of it. The biggest challenge for us in the community, whether you do or don’t have a skilled surgeon, having a surgeon turn down by 1 CT [cardiothoracic] surgeon who does maybe a few surgeries of mesothelioma a year. I don’t think it’s a fair answer to give the answer about surgery vs no surgery from somebody who is experienced, who does tons of those procedures, before you move along with palliative treatment. But this offers hope. Survival rate was fantastic, more than 40%, and I’m excited about it.

 Great. When we talk about this regimen, the next obvious question would be, what is the role of PD-L1 expression? Is there a reason to check PD-L1 expression in mesothelioma patients if you are thinking of ipilimumab-nivolumab? Christine, can you talk a little about that?

In this trial, they did show what the rates of overall survival were for patients who were PD-L1 negative as well as patients who were PD-L1 positive or had PD-L1 expression. The benefit in this trial did seem to be better for patients who had PD-L1 expression, with a hazard ratio of 0.69. However, for patients who are PD-L1 negative, ipilimumab-nivolumab did not appear to be inferior to chemotherapy, which is also important to know.

Fundamentals of Mesothelioma

You mentioned pembrolizumab. One of the other regimens that’s been studied in small-cell lung cancer is ipilimumab-nivolumab. Steve, you were following the ESMO 2020 [European Society for Medical Oncology Congress] conference closely. There was an ETOP [European Thoracic Oncology Platform] study that looked at ipilimumab-nivolumab. Talk to us about that trial.

This was an interesting study, but get ready for a little more disappointment. This was the STIMULI trial presented by Professor Solange Peters, an ETOP study looking at patients with limited-stage small cell. Our focus has been on extensive stage. Limited stage is about a third of our patients, and while we can deliver curative chemoradiation, we’re not very good at getting those cures, and most patients, unfortunately, do relapse and still die from their disease. This was looking at patients with limited stage who had completed therapy, looking at consolidation treatment—a maintenance or consolidation immunotherapy approach. You’re randomized to receive nivolumab-ipilimumab, 4 cycles at the higher dosage of ipilimumab at 3 mg/kg every 3 weeks, with nivolumab at 1 mg/kg every 3 weeks, and 4 cycles of nivolumab-ipilimumab followed by nivolumab maintenance. The control arm was just observation, looking at immunotherapy after treatment for chemoradiation vs observation.

This was a negative trial. We did not see an improvement in survival. The hazard ratio was 1.06. Giving nivolumab-ipilimumab in that setting did not improve outcomes. Firas Badin had mentioned earlier the CheckMate 451 study, with nivolumab-ipilimumab failing to improve outcomes after induction chemotherapy in the extensive-stage setting, and we see the same thing here. Whether that’s building on patient selection; it’s the use of CTLA4 in small cell, which has been a little disappointing to date; or there are just flaws of the trial, the trial did take a long time to accrue. In fact, it stopped early for slow accrual; we don’t know. We just know that this approach isn’t 1 we need to pursue further.

Yes, that is certainly disappointing. Let’s hope that it’s a different story with the use of PD-1 or PD-L1 in the patient alone in that space. There is an ongoing NRG-LU005 trial with atezolizumab in the consolidation setting for limited-stage small-cell lung cancer, and my understanding is that trial is accruing fast, reflecting the large amount of interest we’ve got in this space.

I think that’s the important study, and limited stage needs to have better outcomes. There are 2 big studies now. You mentioned NRG-LU005; that’s looking at atezolizumab with chemoradiation followed by atezolizumab maintenance. It combines the benefit we saw in PACIFIC from using of I/O [immuno-oncology] after radiation with the benefit we saw in IMpower133 by adding PD-L1 to chemotherapy. We also have the ADRIATIC study, which is in the same family as PACIFIC, and that’s looking at durvalumab alone or durvalumab with tremelimumab as consolidation after chemoradiation. I don’t think the ETOP study nullifies the validity of these studies. These are important questions; there’s a lot of rationale. These are big, well-powered studies that will hopefully give us an answer as we look to improve outcomes in that subset.

Absolutely. We’ve had very limited progress in the limited-stage small-cell lung cancer space as well. For a long time we were looking at the dose of radiation twice a day vs every day. Unfortunately, we haven’t seen any major differences there. Twice-a-day radiation continues to be of interest and potentially applicable for some patients. There was a trial reported at ESMO that looked at patient-reported outcomes with twice-a-day vs every-day radiation. Steve, what did you learn from that study?

You’re referring to the Bjørn Henning Grønberg study. This was an interesting study that never sat right with me. This was looking at high-dose twice-a-day radiation vs standard dose, 60 Gy vs 45 Gy, and we saw earlier this year the delivery of high-dose improved outcomes and survival. One-year survival was comparable, but a 2-year survival difference was quite significant, which was under the radar for me. But delivering more radiation in the limited-stage setting in a twice-a-day approach is improving survival. One would expect that the improvement in survival would come at the cost of much more toxicity, going up to 60 Gy in a twice-a-day fashion. But that initial presentation did not show a lot of difference in toxicity, which didn’t sit right.

At ESMO this year, we saw some patient-reported outcomes from that study. Sure enough, while the twice-a-day high-dose radiation did improve survival, we saw that the health-related quality of life was good in both arms, supporting that this can be delivered safety. There was more toxicity, specifically more radiation-induced dysphasia with that higher dose, but it does seem feasible. We want to see these replicated in a larger study, maybe in a more international or a US study. But these are compelling data that altering the dose of radiation and delivery fashion could improve outcomes.

Great, thank you. This has been a great discussion on small-cell lung cancer. We now have chemotherapy plus I/O as the standard frontline approach with atezolizumab and durvalumab being approved agents in this setting. In the second line, we have a new drug in lurbinectedin, which is FDA approved. Hopefully, these advances will catch on in the limited-stage setting, where survival rates have remained flat for a couple of decades now.

Trials in Limited-Stage Small-Cell Lung Cancer

 When patients get the chemotherapy–I/O [immuno-oncology] approach—and they benefit for some time, and down the road, maybe 6 or 8 months later, the patient progresses—in the past, we would rechallenge them with a chemotherapy doublet again, right? This was when there was no maintenance. If you give chemotherapy for 4 to 6 cycles, and 6 months later the cancer progresses, we look at how did the patient do the first time around. If they did well, we rechallenge them. Is that approach going to change based on what these trials tell us, or will we continue to rechallenge them with platinum?

I’m smiling because it has happened to me, and I did rechallenge with mine. But my cutoff is 6 months; that’s my minimum cutoff. If they’re closer to a year, I feel more comfortable with it and I have rechallenged with platinum. Do I continue the immunotherapy in that portion? Do I think it’s doing anything? I don’t know if it’s doing anything. I do continue it. That’s not based on any evidence, but just more admitting that the outcomes are quite poor overall. In those settings, I rechallenge and I continue the maintenance, although it’s certainly an area in which we need more trials.

Christine, what’s your approach in that situation?

I have also rechallenged if they recur more than 6 months. If less than 6 months, we’re oftentimes looking for a clinical trial option for that patient.

Certainly. Is the approach in Florida any different, Martin?

 Obviously 6 months is a time frame in which I feel that platinum sensitivity can be rechallenged. I do what Stephen does without evidence; I continue the backbone of immunotherapy. I just basically readd it. These are data that are probably 30 years old, or 20 years old. The rechallenges are based on a certain time cutoff, but we have new options. We have a long-term survival population now, we have a strong interest in clinical trials with antibody-drug conjugates, and lurbinectedin is another option that has entered the arena for both platinum-refractory disease and platinum-resistant disease on almost an equal basis. There seems to be a different angle of resistance that is independent of the responsiveness to platinum. That would be, in my opinion, a strong second-line candidate.

It depends on the clinical context. If they’re doing well, you have a better option with the rechallenge of platinum, but acknowledging that the response rates significantly drop the closer you’re near the last cycle of treatment, lurbinectedin becomes more attractive. The response rates were around 40%. Responses were not very durable. The toxicity profile wasn’t easy, but it was one that overall, in the greater context, was clearly a new addition and certainly has replaced topotecan in the second-line setting as my standard go-to agent.

That’s great. It’s good to have a new drug approved in the second-line space after a very long time. Admittedly, lurbinectedin is based on a single-arm trial that you mentioned. I was impressed by the fact that the response rate in the chemotherapy-refractory patient population was 25%, and the chemotherapy-sensitive group was 45%, myelosuppression being the main toxicity. We’re beginning to give this in our clinic. I don’t have a lot of personal experience yet. Steve, have you given it? What are your thoughts on the lurbinectedin study?

One of the big pluses of giving lurbinectedin is that it’s not topotecan. I mean, this was a drug that was the standard for decades, approved in the 1990s, and it’s not a drug that we like giving. There’s a lot of toxicity. It’s a really tough schedule: It ties up a chair for 5 consecutive days, and patients don’t feel well when they’re receiving it. Lurbinectedin has a more favorable schedule and more activity, and there is toxicity; it’s a cytotoxic drug. It’s much better tolerated than topotecan, and there’s a lot of value in that. As you mentioned, I was most impressed by that chemotherapy-refractory response rate. With topotecan, our response rate in that setting was close to 0. To have a drug that’s going to get responses there, where patients are often symptomatic, is a real welcome addition to our arsenal.

Christine, anything you want to add to what Steve mentioned?

No. It’s just nice to have something else to present to the patients. It felt like historically with topotecan, you’re saying this drug is going to make you feel terrible. It’s going to take away all your blood counts, and your chance of having success is 5%. It’s just nice to be able to present a much more enticing option to the patients.

This is also the setting where we’ve seen a lot of promising drugs fall away. Amrubicin, about 15 years ago, was a very promising drug, but it did not play out in phase 3 trials. Rova-T [rovalpituzumab tesirine] was another promising monoclonal antibody with the antibody-drug conjugate platform, and that did not, unfortunately, play out. It’s good to have a drug that helps patients. We’ll wait to see the phase 3 trials with lurbinectedin, and hopefully they will confirm the efficacy data that we’ve seen in the phase 2 setting. We also have pembrolizumab approved in this space, for patients who progress on prior chemotherapy. Admittedly, the trial that led to the approval was done in the pre–chemotherapy-I/O days. Where does that fit in in the landscape now? Let’s assume a patient got chemo-I/O in the front line, has seen lurbinectedin in the second line, and has progressed on the third line. Would someone feel that pembrolizumab would be appropriate and reasonable to try in this setting?

If we go back to the experience from non–small cell lung cancer, even with crossover sequence matters, and if you didn’t derive a benefit in the first-line setting, where you’re probably in the best physical condition, I believe that PD-1 or PD-L1 followed by PD-1 is probably not a reasonable concept. This may be an option to palliate your mind, but this is not very evidence based. You have to acknowledge that in the third-line setting, with the current algorithm that Stephen established, we don’t have anything to offer outside a clinical trial.

Treatment for Progressive Small-Cell Lung Cancer

Where does PD-L1 expression stand in small-cell lung cancer? Is this something you test in your routine clinic? Martin, let me ask you that question and then have Christine chime in as well.

 That’s the million-dollar question. We don’t have any biomarkers. I used to be more aggressive about sequencing small-cell lung cancer, and my experience was surprising to me, that a large portion of small-cell lung cancer is actually TMB [tumor mutational burden] low as well. They have hallmark mutational changes in the retinoblastoma and the 

 gene but are sufficient in mouse models and in humans to actually lead to a small-cell transformation in the right neuroendocrine precursor cell. It’s not surprising that despite the typical heavy-smoking background, there’s very little efficacy.

I don’t have any biomarker answer for you. This is typically a very difficult-to-biopsy lung scenario if they have them, and we just have to basically go back, and some of that work has been done, to look at that 10% benefiting population and the long-term surviving or long-term benefiting population, that may be different whether up front or in the long-term maintenance setting. But for most patients, the vast majority of benefit is driven still by carboplatin. There’s not a big difference between the platinum agents. This is more to allow for international enrollment where cisplatin is more frequently used than in the United States, in the palliative setting.

We’re far away from finding 1 true biomarker that would characterize PD-L1 or PD-1 benefit in the population, and the trials overall look so interchangeable. One of the things that was interesting for durvalumab and that makes me spring toward the CASPIAN regimen is the difference regarding whole-brain radiation as an intervention, where it was more optional. This will be 1 of the trial design changes. But overall, the hazard ratios and the outcomes are almost interchangeable between the 2 trials.

Thank you. Christine, a not-infrequent clinical scenario is you’re on the consult service, and you’re asked to see a patient diagnosed newly in the hospital. It turns out to be small-cell lung cancer, and there is a need for a clinical reason to start the patient on treatment right away. How do you approach that situation?

The way I have handled this is to give cycle 1 of chemotherapy inpatient, and just add in the immunotherapy with cycle 2. We’re not sure exactly how that would change the long-term outcome of the patient, but certainly for practical reasons, just to get the patient started on treatment, get some chemotherapy in their system, and then have the flexibility to add the immunotherapy and go through the insurance approval process in a more calm setting as an outpatient is something that has served me well.

Thank you. When we give this chemotherapy-immunotherapy approach, all these trials have used the I/O [immuno-oncology]as a maintenance treatment after they complete chemotherapy. Is that something you all routinely do in the clinic?

 No. We did a very large study, CheckMate 451, nivolumab and nivolumab-ipilimumab as a maintenance treatment after platinum doublet. I thought it was going to give us some hope for our patients; unfortunately, that study came back negative. For a patient who gets started on triplet, whether durvalumab or atezolizumab-platinum doublet, I tend to keep them on maintenance treatment like the study design. But I’m going to give the survival advantage the 25% or 30% reduction in risk of death, and I tend to do the same thing they’ve done on the trial. I tend to keep my patients on a single agent, either atezolizumab or durvalumab, as a maintenance treatment.

Thank you. Steve, when you talk about I/O agents in patients with small-cell lung cancer, where we see paraneoplastic syndromes, is there any change in the tolerability profile of the chemo–I/O combination for small cell compared with what we see in non–small cell lung cancer?

 Not that I’ve seen. Patients with severe paraneoplastic syndromes were excluded from those registrational studies. We don’t have clear answers there. If someone had a myasthenic crisis, for example, it probably wouldn’t be likely to give that patient immunotherapy across the board. But endocrine paraneoplastic syndrome is common in small-cell lung cancer. Really we haven’t seen any worsening. A lot of times the course of those conditions mirrors that of the cancer itself. Once you get a response, those can improve. I haven’t seen any difference in tolerability. It was something we were concerned about, but I haven’t seen evidence to point me in that direction.

Treatment Options in Small–Cell Lung Cancer

Let’s talk about the recent advances in small-cell lung cancer. For almost 3 or 4 decades, we used chemotherapy as the frontline treatment for this disease, platinum-etoposide being the platform regimen. Now we have a new standard of care in the form of chemotherapy plus immune checkpoint inhibition. We have 2 approved drugs in this setting, atezolizumab and durvalumab, in combination with chemotherapy. Firas, let me get your thoughts on, briefly, the high points of the data and some of the recent updates we heard at ESMO 2020 [European Society for Medical Oncology Congress].

As you mentioned, it’s been a long time since we had any breakthroughs in small-cell lung cancer, despite the wide adoption of immunotherapy as well as target treatments in non–small cell lung cancer. It seemed as if we were stuck with small-cell lung cancer platinum doublet first line followed by topotecan second line, until these 2 nice randomized studies, the IMpower133 as well as the CASPIAN trial. Fairly similar design, very similar patient population, first-line small-cell lung cancer, extensive stage, treatment-naïve, randomized to receive either standard chemotherapy, platinum-etoposide, vs the same chemotherapy with atezolizumab in IMpower133 or durvalumab with or without tremelimumab in the CASPIAN trial. Both studies showed an overall survival advantage with the addition of PD-1 or PD-L1 inhibitors in first-line small-cell lung cancer.

With the updates from ESMO, they tried to look at those patients who had done very well, who had extended long-term survival, and see why did these patients have or who are those patients who had extended long-term survival. Both trials also had similar findings. I’m not surprised that of patients who did receive immune checkpoint inhibitors, the group who had the triplets had more patients who achieved longer term of survival, as well as patients who had fewer brain metastases, fewer liver metastases, and excellent performance status, as well as women. There were more patients in those categories who had more extended long-term survival.

There are still a lot of things that we need to learn from small-cell lung cancer. I don’t think we have appropriate biomarkers for treatment in this difficult disease, but it’s good to have options today for our clinic for those patients with this bad disease.

 Certainly. Steve, you were one of the PIs [primary investigators] of the Impower133 trial that studied atezolizumab in combination with chemotherapy. How have these trials changed your practice?

 It’s our new standard of care. I appreciate that the hazard ratio is not 0.1, but I know that the 5-year survival is not 90%. I know it’s not as good as we had wanted. There’s no question in my mind that it’s clearly better than what we had and deserves to be our new standard. What we’re learning as more data come out is that we have no way to identify who those patients are. Whether it’s TMB [tumor mutational burden], PD-L1, we simply don’t have utility in patient selection, and right now it is an all-comer approach. I get that that’s frustrating when we know the benefit is carried by a subset. Today the only way to make sure that subset gets the treatment is to offer everyone the opportunity to get immunotherapy. But we need to build on that, whether it’s newer, more novel, more expansive combinations on that backbone or finding treatment using subtypes, for example. A lot of the work at your own institution is done on different transcriptional subsets of small cell.

 Christine, we all have the first drug approved with atezolizumab and chemotherapy, and we started using it. Then came the CASPIAN results. Talk a little about potential differences you see between these 2 trials. How do you adopt the CASPIAN results and the durvalumab approval in your clinical practice?

I have used the CASPIAN regimen, durvalumab. Initially, I just wanted to get experience using another drug and to have that experience in my back pocket. Looking at the clinical trials, I don’t find that there’s a huge difference between the trials as far as efficacy or patient selection for 1 drug over the other. What it does is it gives me a second large randomized trial that has a positive outcome, to ensure that this is a really positive benefit of the addition of checkpoint inhibition in addition to chemotherapy for these patients with extensive-stage small cell.

 One of the things that was different between these 2 trials was 1 of the studies, the CASPIAN, allowed both cisplatin and carboplatin use. What extent does having cisplatin or carboplatin in the combination regimen influence the outcomes in your impression?

To me, it allows for additional provider input and additional provider decision-making in that capacity. If you had a very compelling reason why you wanted to use cisplatin over a carboplatin for, let’s say, less myelosuppressive activity or some other reason, it gives you that option. That’s just nice to have as a provider, to have as many options in your arsenal as possible.

 Absolutely. One thing I would say, when you look at the results of both of these trials, the numbers look like what we talked about earlier in non–small cell lung cancer: very similar in terms of clinical benefit with PFS [progression-free survival] results. I would also add in the pembrolizumab trial reported at ASCO [American Society of Clinical Oncology Annual Meeting] by Charlie Rudin and the ECOG-ACRIN trial reported by Dr Ticiana Leal with nivolumab in combination with chemotherapy. Just about every 1 of these studies showed very similar overall survival and hazard ratios. Technically, the pembrolizumab trial did not meet the statistical significance for overall survival, but if you look at the hazard ratio, it’s not very different from what we’ve seen with other drugs. In the randomized phase 2 chemotherapy-plus-nivolumab regimen, once again we saw very favorable PFS and overall survival results. These drugs in combination with chemotherapy are behaving differently, and as it was pointed out—Steve, you mentioned this—the benefit is modest. Still, we have a lot of work to do, and 1 possible approach is biomarkers. Are there biomarkers that can be used?

Recent Advances in Small-Cell Lung Cancer

How do you manage a given patient in your clinic? These don’t have to be long answers, just a quick choice of what would you do for a patient, let’s say a 70-year-old male with stage IV nonsquamous lung cancer, who has a good performance status. We talk about 3 scenarios: a patient with PD-L1 expression greater than 50%, 1% to 50%, less than 50%. Let’s talk about what’s your treatment of choice for that particular patient. Steve, greater than 50% PD-L1 expression, frontline treatment, what would you select?

: My standard right now is PEMBRO [pembrolizumab] monotherapy, and I use the every-6-weeks regimen. There’s some advantage to having patients come in less frequently. I personally have had good outcomes with it. My standard is pembrolizumab monotherapy for PD-L1 high. For PD-L1 low, it’s pembrolizumab/chemotherapy for me. The chemotherapy/IO [immunotherapy] combinations provide a benefit across PD-L1 strata. I like the combinations for the low. And for PD-L1 negative, even though off label, I am using more NIVO/IPI [nivolumab and ipilimumab] in that setting. Really good outcomes there in that PD-L1 negative. The duration of response is compelling there. The outcomes again across subsets, a little better for the PD-L1 negative and the PD-L1 low. I don’t have a great reason as to why, but that would be my standard today. It might change tomorrow.

: For PD-L1 high patients, I start with pembrolizumab monotherapy, with a short interval CT scan at 6 weeks to make sure we’re headed in the right direction. For PD-L1 expression of 1% to 49%, I do use combination carboplatin, pemetrexed, and pembrolizumab, and then for PD-L 0%, it’s either triplet combination chemotherapy/IO versus ipilimumab/nivolumab based off of patient characteristics and also patient preference.

: I would add a clinical selection, we didn’t get into this with CheckMate-227, but a patient selection based on the symptomatology and tumor volume is a major factor for the up-front well-being of a patient. Six weeks may be a little bit earlier than what I would scan. But we’re all in agreement that the first 3 months decide the fate of a patient with immunotherapy. If I have a feeling that somebody were to deteriorate early, I would always add chemotherapy, independent of PD-L1 level. They need 6 to 12 weeks in my opinion, to give immunotherapy a fair shot. If I have somebody who has high PD-L1, meaning greater than 50%, and low symptomatology, I think PD-L1 plus ipilimumab or PD-L1 alone are reasonable options. If I have PD-L1 low versions, from 1% to 49%, that’s chemoimmunotherapy or ipilimumab/nivolumab, depending on preference. The same is true for the PD-L1 negatives. They stand square side by side in terms of what we want to look at. But what this discussion highlights is that with all these different concept options, that we need a trial that really compares these side by side, so that we know how they individually work out in their respective fields of study. The studies are close enough to draw some conclusions, but not to have a strong comparison, which is why our regimens all look a little bit different and they’re probably all on the reasonable side.

: It’s easier to say what we don’t use than what we use because we have a lot of options. I can tell you, I rarely use chemotherapy in strongly positive PD-L1. Most of us, unlike my colleagues, I will either do pembrolizumab alone or nivolumab/ipilimumab in strongly positive PD-L1. In PD-L1 negative, I tend to do combination, either IO-IO, nivolumab/ipilimumab, or chemotherapy plus IO. And then 1% to 49%, again the same thing, it depends on the patient. It depends, like Martin mentioned, symptomatology and how fast you would like to get a response. But I’m moving away from chemotherapy, and I’m using more immunotherapy, either pembrolizumab alone or nivolumab/ipilimumab now.

: Great. This nicely summarizes where we stand in terms of frontline treatment of non–small cell lung cancer for patients who don’t have a driver mutation. I want to thank our panel for discussing all the exciting new abstracts.

Treatment for PD-L1 High/Low/Negative Non–Small Cell Lung Cancer

Steve, as you talk about recurrence and second-line treatment options, we saw an interesting study at ESMO [the European Society for Medical Oncology 2020 meeting] called the PIONeeR trial, which looked at later lines used, but was a biomarker-focused trial. Tell us about that study.

I like this study. It is important work, and this is not a therapeutic study. This was presented by our colleague, Fabrice Barlesi, MD, PhD, and is looking at patients who are receiving immunotherapy with either nivolumab, pembrolizumab, or atezolizumab in a second-line setting, or in combination with chemotherapy in the frontline setting. This was not an intervention study. Patients had a repeat biopsy and blood samples, trying to understand the science of immune responses and if we can understand better what’s happening. When we look at these drugs, they’re superior to chemotherapy. We see long-term survival and amazing results. People are startled to understand how little we understand about exactly how these drugs work and why they work in some and not others.

This is looking beyond PD-L1, and they saw some interesting things there. While PD-L1 did serve as one predictive marker of who’s benefitting, they saw an important role for tumor infiltration by cytotoxic lymphocytes, building on work done by our colleagues in melanoma, where if you have more immune cells within the tumor, those patients seemed to derive those antitumor immune-mediated responses, and high infiltration of regulatory T cells, coupled with weak PD-1, seemed to associate with worse outcomes. It’s not just activation through the PD-1/PD-L1 pathway. Those activated immune cells need to get to the tumor, infiltration into the tumor, and this type of biomarker-specific work is critical to increasing the sophistication of delivery for immunotherapy.

Yes, interesting, and it will be nice to know if you have a tumor that’s not responding, what can be done to increase the infiltration of T cells and to provide the right kind of microenvironment for those patients to respond better to therapy. This also brings up the importance of asking the question about the immune microenvironment and how that reflects the patient’s likely response to immunotherapy. We’re seeing some information here from various trials.

One study that I thought was informative is the subset analysis looking at the genomic characteristics of the tumor and how that relates to outcome. This was a subset analysis from IMpower150. This talked about the role of 

 mutations. These are mutations we see in lung adenocarcinoma, and 

 we see in squamous as well. It’s traditionally been thought that these mutations would be associated with poor outcomes with immune checkpoint inhibition, based on prior experience.

At the ESMO meeting, the IMpower150 investigators looked at the tumor samples in a subset of patients who had the 

mutations, and what was interesting is these mutations definitely have a prognostic impact, but the chemotherapy plus bevacizumab plus atezolizumab regimen was still better for 

 mutations compared to what they saw in degree of benefit in the wild-type population. There’s also something that we’ve seen with the pembrolizumab-based studies looking at the impact of 

. We’re still learning more about various genomic events that might either sensitize or portend a poorer outcome with immune checkpoint inhibition.

I couldn’t help but talk about TMB [tumor mutational burden] when we discuss biomarkers, and I want to turn this question to you, Christine. What do you think about TMB as a biomarker in this situation?

: There have been a lot of challenges with using TMB as a biomarker, as I’m sure all of my colleagues on this panel have also appreciated. One of the biggest issues that we’ve had is standardization of TMB across platform and between institutions. It’s hard to know how to apply a nonstandardized biomarker to some of this information. We’d all been hoping that TMB was going to pan out as far as a complement to PD-L1, giving guidance and putting patients into buckets of high PD-L1, low TMB, what does that mean, how can we choose our therapy? But unfortunately, it doesn’t appear that we’ve had quite as much efficacy using TMB as a biomarker as with PD-L1.

: Any other thoughts on the TMB issue? Steve?

Part of the reason why we keep coming back to TMB and why we won’t let these negative studies put the issue to rest, is it just makes sense. It’s a rational biomarker. When we have more somatic mutations, you expect more neoantigens, and you’re just increasing the odds that you have a T-cell receptor that’s going to interact. It’s such a rational biomarker, that it seems like it should work despite evidence to the contrary, and we need to continue to refine that. But as of today, it doesn’t influence my treatment practice.

Understanding Immune Response in Non–Small Cell Lung Cancer

For us, having heard this, who would use the chemotherapy plus IPI/NIVO [ipilimumab/nivolumab] approach, and if you choose that approach, is 2 cycles of chemotherapy, in your impression, sufficient?

 Suresh, before I go to the chemotherapy/nivolumab/ ipilimumab, the nivolumab/ ipilimumab combination has proven itself in multiple other tumor types prior to the non–small cell lung indication. We’ve seen that in melanoma, we’ve seen that in GI [gastrointestinal] and renal cell carcinoma, and here it is the same story in non–small cell lung cancer. If you believe the science behind this combination improving the function, as well as the quantity of the T cells, then you would expect to see better results with this combination. What is interesting about this combination, it tends to overcome histology, it tends to overcome PD-L1 suppression, since we’re seeing the same results regardless of histology as well as regardless of PD-L1 status.

Now back to your question on the combination of I/O [immunotherapy]-I/O plus a platinum doublet, the CheckMate 9LA protocol, I was one of the primary investigators on this study. It’s a very nice, well-designed, phase 3 clinical trial looking at the standard of care chemotherapy platinum doublet vs just 2 cycles. This is a novel approach. We’ve never done just 2 rounds of chemotherapy, we tend to do 4 to 6 cycles, that’s the standard in our clinic. But it’s a novel approach with only 2 doses of chemotherapy, trying to get some of the synergy from chemotherapy, plus Opdivo [nivolumab] and Yervoy [ipilimumab], and then patients will go into Opdivo/Yervoy maintenance.

The dosing is different. Yes, we’re used to giving Opdivo/Yervoy in our clinic, but we’re not used to giving Yervoy at the lower dose, but I don’t think any of my colleagues here will argue against a lower dose of Yervoy. I think we’re just going to give enough of the drug with limited toxicities or adverse effects. It was only 1 mg/kg every 6 weeks. Then the primary end point is to look at progression-free survival as well as overall survival, and the study did meet its primary end point, and about two-thirds of patients are still alive at 1 year with this quadruplet regimen.

Now, is this an appropriate regimen for everybody? I don’t think so, but definitely it’s a good option. If you don’t want to miss the opportunity of using chemotherapy in the first-line setting, but at the same time you don’t want to give the full force of 4 to 6 cycles, then here is another option for our patients.

Great. As we talk about these new regimens, we don’t want to forget the ones that we’ve already had in the clinic. In fact, we heard about long-term outcomes with pembro [pembrolizumab] in the high PD-L1 expression population. For us, this was the update at ESMO [the European Society for Medical Oncology annual meeting] about the KEYNOTE-024 study. Can you talk to us about those results?

This is a dear study to my heart because it was the first time that we were able to use a checkpoint inhibitor as a single agent for patients with metastatic non–small cell lung cancer across different histologies, but in patients who have strongly positive or a high expression of PD-L1, more than 50%. We all are aware of the initial data with the trial having an overall survival advantage compared to platinum doublets, but here we have the 5-year data. We’re always talking about flattening the curve with COVID-19 [coronavirus disease 2019] and we’re doing the same thing with lung cancer. We are trying to flatten the tail of the curve with lung cancer, we want to see long-term survival. We start to wonder if we are curing some of our metastatic patients with immune checkpoint inhibitors or with immune therapy, and with this study, more than one-third of patients who received pembrolizumab in the first-line setting are still alive. These are wonderful data.

You mentioned, Suresh, the 3-year data also of Opdivo/Yervoy. We’re seeing more long-term survival. You look at numbers, 5-year survival with chemotherapy for those patients, 5 years ago you were seeing about 0%, or definitely less than 5%, and here today we’re talking about one-third of patients are still alive at 5 years. That’s wonderful.

What’s also nice to see with the trial, there were no added toxicities, nothing out of the ordinary. We’ve learned from different trials that immune-mediated reactions, if they are going to happen, they tend to happen early, usually in the first 6 months. They could happen at any time, but are more likely to happen in the first 6 months rather than later, which allows us to continue treatment beyond that period.

Absolutely. It is amazing that we have a third of the patients make it beyond 5 years. There was a discussion whether that represents a cure, and Roy Herbst, MD, PhD, the discussant for that abstract, certainly said those patients are cured. The important message there is you give 2 years of therapy and you stop. If the patient progresses, reintroducing the drug was associated with activity there, so that’s what I have done in my clinic for those patients. Steve and Christine, how do you approach that situation, when they progress on immunotherapy?

In similar fashion to you, I first rechallenge with immunotherapy, single agent, and do a short interval CT scan. I’ll take a peek at 6 weeks to make sure we’re headed in the right direction. But seeing another set of data about rates of efficacy at reintroduction, I’m comfortable. The majority of patients had either a response or at least disease stability, so this also helps me feel more comfortable in coaching patients in that decision at 2 years of whether to stop therapy, because I think that’s a huge point of patient anxiety in their treatment course. They’ve been told they have metastatic lung cancer, then they’re told they have this miraculous immunotherapy option. They get disease control for 2 years, and stopping the drug is such an anxiety-provoking episode for them. Now it’s nice to have some additional data to give them about, “OK, well if the cancer does come back, here’s what we would do, and here’s the likelihood of success in that case.”

: I agree with that. Fortunately for me, it hasn’t happened yet. All of my patients who have gotten to 2 years where I’ve stopped, it simply hasn’t recurred. I like having that assurance, but so far, so good. Ultimately it’s not going to be a one-size-fits-all. I think there probably are predeterminants of who can stop early and who can’t, of who needs specific strategies. All of my patients who have made it to 2 years and we’ve stopped electively, their disease remains in control now off therapy.

Chemotherapy and Immunotherapy in Non–Small Cell Lung Cancer

Another regimen that enters the landscape, I want to hear, Martin, your overview of the CheckMate 9LA trial.

This is a 2-part study with PD-L1 positive, overlapping with the pembrolizumab approval for greater than 1% in the PD-L1 negatives. I want to start with the positive ones. This was a 3-arm study looking at chemotherapy as the comparator arm and then nivolumab, and then nivolumab plus ipilimumab, and there were incremental benefits. Both were better than chemotherapy, but particularly interesting for me in the overlap of the intent-to-treat population, but also in the individual subgroups, a benefit of the combination immunotherapy [I/O] over the nivolumab arm alone, which suggests to me that single-agent PD-1 is not covering exactly the entirety of our needs in our population, and that there is utilization and benefit to our original immunotherapy agent, which is ipilimumab. It’s been around for 9 years and finally is making its way into non–small cell lung cancer. This is interesting. If you will allow for the discussion from earlier that our PD-1 inhibitors are similar and are performing similarly, there is at least an absolute numerical benefit to using the combination if you choose to have a chemotherapy-free regimen for the PD-L1 positives.

What was even more exciting to me is the question of can you utilize immunotherapy alone in a population that has previously only produced negative results? CheckMate-026 was the hallmark trial that defined that we need at least some positivity of PD-L1 for benefit. There’s a bimodal distribution between the PD-L1 highs and the PD-L1 negatives, but ipilimumab serves as an immune sensitizer that further enhances and stimulates toward a PD-1 response. From a relative benefit standpoint, for a PD-L1 negative patient who is interested in immunotherapy, this is a suitable regimen. I was disappointed when the FDA didn’t approve the PD-L1 negative population. This would be a great option for this patient population where we typically see little benefit of the addition of single-agent immunotherapy. It would be interesting.

If you allow for that comparison again, chemoimmunotherapy, ipilimumab/nivolumab looked good in comparison. Those were 2 arms, and it was originally scolded for being a complex trial, but in the end it turned out to be one that carried a number of valuable lessons, which is ipilimumab/nivolumab can be competitive in the PD-L1 positive space as a combination, it can be competitive against chemoimmunotherapy in the PD-L1 negative space. This is going to be hard to argue that this wouldn’t be a strong consideration for every patient in the PD-L1 continuum.

 When we talk about this combined PD-1 and CTLA-4 blockade approach, one of the concerns people typically have is about tolerability and safety of this combination. My view, looking at both the CheckMate-227 and 9LA data, is that the combinations are tolerable, and early recognition of adverse events related to autoimmune phenomena can be managed, and patients can go on to complete therapy. Martin, we saw some results of patient-reported outcomes for the CheckMate 9LA trial recently. Can you talk to us about that?

 CheckMate-227 has been, at least for non–small cell lung cancer, in a new dosing regimen. This is ipilimumab, 1 mg/kg body weight. We started at 3 mg/kg body weight in the melanoma setting, and in the adjuvant setting, even 10 mg/kg, and now at 1 mg/kg in non–small cell lung cancer. This is a dosing sweet spot, where you maintain an immune response, but your adverse effect profiles look substantially better, especially the GI [gastrointestinal] toxicities are now in the single digits in the grade 3/4 events, which is substantially lower than what we’ve seen with higher doses before. The 1 mg/kg body weight makes this a completely new setup.

This also relates to the fact that we must reconsider the reputation of this agent. This is an immune-sensitizer. This relates to the patient-reported outcomes, which are substantially better in terms of general quality of life for patients compared to chemotherapy, which is not surprising that if you prevent the cytotoxic adverse effects that are not liked by patients as well as clinical deterioration, that you would have patients that are overall doing better. My impression of this is that this is a well-tolerated regimen both in the combination setting with chemotherapy, where you have a limited addition of chemotherapy, as well as in single agent, and should be given a second look based on the new dosing.

: I would like to hear the opinions from some of our other participants on this panel about where they see a role for the I/O-I/O approach in non–small cell lung cancer in the frontline setting, given the data and the approvals we’ve seen with that. Steve, starting with you.

 It’s compelling. There are a lot of reasons why this is an appealing regimen. When I introduce this regimen or discuss it with my patients, while I will mention that this is a chemotherapy-free regimen, and there’s a lot of interest in that, I’m quick to follow that it’s not toxicity-free, and the grade 3 adverse event rate for CheckMate-227 is very similar to the chemotherapy arm. They’re just different toxicities. You won’t see necessarily the myelosuppression, the alopecia, the nausea that we may see with cytotoxic chemotherapy, but there are still a lot of other toxicities we need to be aware of. I need to find the right patients to use that.

There are a couple of reasons why I might go to a dual checkpoint blockade regimen up front. One would be, as Martin alluded to, that hazard ratio in the PD-L1 negative is compelling. You had mentioned earlier breaking things down by histology. If you look at PD-L1 negative squamous cell carcinoma, the outcomes with chemotherapy/I/O are not good. The CTLA-4 in PD-1, in that arena, arguably has better outcomes across trials. The hazard ratio was much better in the PD-L1 negative than we expected, and that was in part due to underperformance of the chemotherapy, but the chemotherapy arm did worse. The CTLA-4 in PD-1 arm really did the same for PD-L1 positive and negative with a very comparable survival. A very impressive duration of response, it’s compelling.

If all things are equal and you start with dual checkpoint blockade, and if it doesn’t work, if you’re not in that group where you get that long-term survival, now my second-line option is platinum doublet chemotherapy, which I would consider an upgrade over standard second-line docetaxel-based therapies.

 It adds a line of therapy for you when you use the I/O-I/O combination.

 Christine, I see you nodding. I take it that you share that viewpoint that Steve just mentioned.

I absolutely do. We also at the University of Chicago have had an investigator-initiated trial looking at combination ipilimumab/nivolumab and stereotactic body radiotherapy, or SBRT, and that was presented at ASCO [the American Society of Clinical Oncology annual meeting] this year in abstract form. Because of that, I’ve had a lot of comfort giving ipilimumab/nivolumab and managing the toxicities, and also have seen, exactly as Steve was just referring to, the benefits that that PD-L1 population with a 0% expression of PD-L1, seeing the benefits that they can obtain with this dual checkpoint blockade is quite impressive.

One of the other things that I love about this regimen is that time to chemotherapy gets pushed out. You get to save an amazing second-line option of carboplatin/pemetrexed, which has been the backbone of management for these patients for the prior 10 to 20 years. There are a lot of reasons to consider it as a frontline option.

Treatment Options in PD-L1 Positive Non–Small Cell Lung Cancer

We learned about another interesting study in the frontline setting that looked at a newer checkpoint inhibitor, cemiplimab. Steve, what did that study report and what were the implications?

You’re referring to the EMPOWER-Lung 1 study. This is looking at a PD-1 inhibitor, cemiplimab, vs standard chemotherapy as the frontline treatment for PD-L1 positive non–small cell lung cancer. A randomization to a PD-1 inhibitor vs chemotherapy may sound familiar to the KEYNOTE studies we’ve seen, like KEYNOTE-024. What we saw were in line with those results, that PD-1 blockade with cemiplimab improves survival compared to chemotherapy. We saw an improvement in PFS, [progression-free survival] but most importantly, an improvement in survival, the hazard ratio there in the PD-L1 high subset at 0.57. Cemiplimab had a better response rate, a better PFS, better overall survival, and a better toxicity profile, a winner across the board. This was despite having a high crossover rate, in fact, higher than what we saw in KEYNOTE-024. The crossover rate in this study was 74%, reflective of the time where the drug is more widely available. What we’re seeing with EMPOWER-Lung 1 reaffirms what we’ve seen with other PD-1 inhibitors in this space.

Another PD-1 inhibitor, it’s probably the third drug. We have PEMBRO [pembrolizumab] and ATEZO [atezolizumab] already approved in this space, and cemiplimab shows data. Having seen these data, Christine, do you notice any remarkable differences between one drug vs the other?

There aren’t dramatic differences that I’m appreciating between the 3 drugs and what we’ve seen in the trials. I have a tough time moving away from what has become standard as pembrolizumab in the frontline setting to seeing a large advantage of cemiplimab over what we already have.

One interesting feature about this study was there was a high number of patients with squamous cell carcinoma in the EMPOWER study, about 45%. Is there a difference in efficacy of I/O [immunotherapy] agents between squamous and nonsquamous histology? Martin and Firas, I would be curious to hear your thoughts on this.

Squamous cell carcinoma is a more immunotherapy-sensitive disease. The correlation with smoking, higher TMB [tumor mutational burden], and inflammatory markers is probably more stringent than for adenocarcinomas. They all exclude 

, but I’m not certain that they all have a full biomarker assessment. Are all PD-1s made the same? I know that we have questions about the PD-L1s. But I have to say that the data, despite the crossover rate, the hazard ratios are better, the absolute numbers are better, so I don’t want to put the topic to rest. I’ve looked back at other disease spaces where cemiplimab was performing quite well, but there may be differences between the individual PD-1 inhibitors. Cemiplimab was designed following nivolumab, it’s a second-generation PD-1, and there may be a difference. But squamous cell carcinoma is more set up to provide a meaningful benefit for immunotherapy, especially when you don’t properly select out all the oncogenic driver adenocarcinomas that may be involved in the study.

: I agree with Martin. If you practice where I practice in the tobacco belt, we see a lot of squamous cell carcinoma. There is a difference in responses between adenocarcinomas and the squamous cell carcinomas, regardless of the difference between PD-1 inhibitors. When you combine immune checkpoint inhibitors, PD-L1 status plays a lesser role, as well as histology plays a lesser role. We’ll be talking about some of the combination checkpoint inhibitors. When you’re doing more than 1 immune checkpoint inhibitor, you tend to overcome some of those differences based on PD-L1 status or histology. To me with this study, as Stephen alluded to, the crossover rate was high, and despite that, the survival advantage was still seen. It might argue that if you delayed initiation of immunotherapy, then patients may not do as well. You can add a checkpoint inhibitor down the road after they’re done with chemotherapy, but we’re seeing more evidence that the earlier you adopt immunotherapy, the better the outcomes are.

: I agree with that. If this trial had read out in 2017, it would have changed the world. In 2020, the world has already changed, and to me that lessens the impact. I would absolutely be in favor of an approval here. I don’t know if there’s a lot for me to change my practice. We tend to be creatures of habit, and inertia is a little difficult to overcome. I’ve got my work pathways set up, I’ve got prior authorization routes set up, my EMR [electronic medical record] is set up. I don’t know if I see data that are compelling enough to make me change my practice, but I’d absolutely support combinations building on this or using this as a control in a randomized trial.

Steve, when you said the world has changed in 2020, I thought that was the most understated statement of the year. But we will take that. One thing I found interesting, when you look at these trials, and going back to Christine’s point, what’s different from one another, what’s fascinating is these are trials done with different drugs, in different settings, albeit they’re all patients with first-line non–small cell lung cancer. What you end up seeing is the hazard ratios for PFS and survival almost come together across these drugs, even though we know that there are intrinsic differences from one drug to the other. The consistency of the results is something that gives us confidence that giving frontline therapy for a high PD-L1 patient with a single-agent checkpoint approach is very strong.

Let’s segue into talking about the I/O-I/O combination approach, where we have seen some results in the past few months that are interesting. I can talk about the CheckMate-227 trial, and then I’ll turn it to Martin to talk about the 9LA trial, which are both strategies that combine ipilimumab with nivolumab. I had the pleasure of presenting the CheckMate-227 data at ASCO [the American Society of Clinical Oncology 2020 annual meeting]. This was a trial that enrolled patients with frontline non–small cell lung cancer and randomized them to various treatments based on the PD-L1 expression level. Patients who had PD-L1 expression greater than 1% were randomized to chemotherapy alone vs NIVO [nivolumab] alone vs IPI [ipilimumab] plus nivolumab, and the PD-L1 less than 1% group, the randomization was to chemotherapy alone versus chemotherapy plus nivolumab versus ipilimumab plus nivolumab.

When we look at the comparison of ipilimumab plus nivolumab versus chemotherapy, there was a statistically significant improvement in overall survival, both in the PD-L1 high group and the PD-L1 negative group. The survival hazard ratio was even more favorable in the PD-L1 negative group at 0.62.

We presented longer-term follow-up data from the trial, and the number that comes to my mind is the 3-year survival rate for patients treated with ipilimumab and nivolumab was 33%, both in the PD-L1 high and low group, which is remarkable considering that not too long ago, we were not talking about 3-year survival rates for patients with lung cancer. The combination of ipilimumab and nivolumab is now an FDA-approved regimen. It’s approved for PD-L1 positive patients in the US; NCCN [National Comprehensive Cancer Network] guidelines recommend it for both positive and negative patients.

Durability of response with ipilimumab and nivolumab in that trial was almost 3- to 4-fold higher compared to chemotherapy. If patients had a response with chemotherapy, the duration of response was 6-and-a-half months. With ipilimumab and nivolumab, the response duration was almost 23 months. This suggests that patients who derive response with this combined immunotherapy approach have the ability to maintain that benefit for a lot longer.

Treatment Efficacy in Non–Small Cell Lung Cancer

, “Updates in Immunotherapy for Thoracic Malignancies.” I’m Dr Suresh Ramalingam from Winship Cancer Institute of Emory University in Atlanta, Georgia. Joining me today for this discussion are my colleagues, Dr Firas Badin from Baptist Health in Lexington, Kentucky; Dr Christine Bestvina from the University of Chicago in Illinois; Dr Martin Dietrich from the University of Central Florida in Orlando; and Dr Stephen Liu from Georgetown University School of Medicine in Washington, DC. Welcome everyone to this program.

Today we’re going to discuss a number of topics, including immunotherapy-based treatments in the up-front treatment of non–small cell lung cancer, recent developments in small cell lung cancer, and finally we will finish up with mesothelioma, a disease where there has not been a lot of progress in 2 decades.

We’ve had a number of recent meetings that have provided us with key insights into how we use this exciting group of drugs for treatment of our patients. We’ve had conclusion of ASCO 2020 [the American Society of Clinical Oncology annual meeting], the World Conference on Lung Cancer presidential virtual session, and more recently, the ESMO [European Society for Medical Oncology] 2020 conference. Now because these were all virtual conferences, we have not had a chance to talk face to face, but certainly all of us have been interacting through various platforms to bring to our clinics the exciting advances from these practices.

Let’s begin with frontline treatment of non–small cell lung cancer. This is the setting where we know molecular testing is done for every patient with non–small cell lung cancer, specifically the patients with nonsquamous non–small cell lung cancer. We want to ensure that every patient with a targetable driver mutation is treated with targeted therapy, and there are at least 7 driver mutations with the FDA-approved targeted approaches. Assuming that those patients are not going to be candidates for frontline chemotherapy, we’re going to focus this discussion on patients who don’t have a driver mutation to start with. With that in mind, I’m going to invite Dr Stephen Liu to talk about a study that was reported at ESMO recently, which was the combination of nivolumab with chemotherapy and bevacizumab.

This was a randomized trial for patients who didn’t have 

 alterations, and there are a lot of parallels between this and the approved IMpower150 regimen. That regimen builds on the backbone of carboplatin/paclitaxel/bevacizumab, showing that when you add atezolizumab, we improved outcomes. This was a similar approach, except instead of the PD-L1 antibody atezolizumab, this used the PD-1 inhibitor nivolumab. Patients all received standard carboplatin, paclitaxel, and bevacizumab, with a simple 1:1 randomization to concurrent nivolumab or placebo. After induction therapy, they then received maintenance bevacizumab and continued the nivolumab or placebo maintenance therapy.

We saw at ESMO 2020, that the addition of nivolumab to the carboplatin/paclitaxel/bevacizumab backbone did improve progression-free survival [PFS], a notable improvement there. We had a hazard ratio for PFS of 0.56, clearly improving outcomes. It’s immature yet for survival. We did not yet see a survival benefit—a hazard ratio of 0.85 with a pretty wide confidence interval—but showing some signal that when you add nivolumab to the carboplatin/paclitaxel/bevacizumab backbone, we do improve outcomes.

This whole concept of combining antiangiogenic or anti-VEGF targeted therapies with immune checkpoint inhibition is something that’s widely pursued not just in lung cancer, but in many other cancers as well. We saw another abstract in the same lines, which was the combination of atezolizumab and bevacizumab. What did you learn from that study?

This one fell under the radar, a smaller study presented by Takashi Seto, MD, PhD, but an impressive end point. This was a single-arm phase 2 study, a modest trial, only 40 patients. This trial enrolled patients with PD-L1 high expression non–small cell lung cancer. No randomization, single arm, all patients receiving atezolizumab, the standard PD-L1 inhibitor, but given concurrent bevacizumab. What we saw in these early end points was a high response rate, over 60%. For reference, when we look at PD-1 inhibitors alone in some of our best studies for PD-L1 high, we’re looking at response rates in the upper 30% range. Seeing a response rate of 64% I thought was quite compelling. The PFS, again, immature, a modest study, but we have a 1-year PFS rate of 55%, which is quite impressive. It’s unfortunate this was a single-arm study. I would have loved to have seen a second arm with atezolizumab monotherapy to really see how this stands up. But those high response rates suggest that there may be synergy between these 2 pathways.

Interesting. Christine, when you look at these 2 studies and think about what these data mean to our current landscape in lung cancer, how do you see this? Is this exciting for you? Is this something that tells you there’s more work to be done?

:I do think there’s more work to be done as Stephen alluded to, particularly the trialed atezolizumab and bevacizumab was not a randomized trial. I would like to see that confirmed with randomization against atezolizumab, which as the authors pointed out, is something that’s planned. But the response rate demonstrated in that study is extremely exciting to me. When we talk about triplet therapy, chemotherapy plus immunotherapy in the patients with high PD-L1 expression, one of the arguments that providers will make for using the triplet over monotherapy is if there’s a high response rate that’s needed, you may choose the triplet. But with seeing this high response rate with the addition of bevacizumab to atezolizumab, I wonder if we’ll be able to use angiogenesis inhibitors in a similar fashion, while still sparing more traditional chemotherapy agents.

When you talk about 4-drug combinations, Martin, I would be curious to hear about your thoughts. What can you tell us about the safety profile of these regimens?

There are several considerations. I still have difficulties finding the role for bevacizumab in the first-line setting, and I personally haven’t used it much. There’s a cumulative toxicity profile, they stay within their lane in terms of additional adverse effects, and I’m concerned about cost. But I would like to understand in the first-line setting what’s the contribution to efficacy. The trial atezolizumab plus bevacizumab was interesting, and there’s a lot of thought even from other disease spaces, that the antiangiogenesis may be contributing to an anti–PD-1 effect. But this was a small study with a very PD-L1 enriched population. There was a tremendous contribution from patients who had 75%-plus PD-L1 expression. It’s hard to interpret that information in the context. I would consider the thought that Stephen brought up, that this is a study that is thought-provoking but it needs confirmation in a more controlled fashion. I don’t have a big role for either the nivolumab- or the atezolizumab-based bevacizumab trials at this point.

Thank you. Firas, anything to add there with regard to this strategy from your standpoint?

I agree with my colleagues. They are interesting data. In our thoracic clinic, we’re moving away from single-agent PD-1 inhibitors into combination treatments, but we haven’t found the best dancing partner yet with PD-1 inhibitors. Is it anti-VEGF treatment? Is it anti–CTLA-4? Is it chemotherapy? I think it’s exciting. Nobody knows the data yet. One of the questions that came to my mind is, is there a particular subgroup of patients that might need a quadruplet, because as Martin reviewed, it’s not only the adverse effects, but also the financial toxicity about giving 4 drugs all at once for those patients. We know from previous studies that patients with liver metastases might do better with quadruplet regimens, with anti-VEGF plus anti–PD-1. We need to wait and see and have more data. But it’s exciting to see these kinds of combinations.

Suresh S. Ramalingam, MD, Winship Cancer Institute

Articles