Let’s get back to these patients. They get on durvalumab, 6 months into treatment they progress. Roy, what do you do in that situation?

Well, they just won. But in clinical practice, then you’re usually in a tough situation because not only have they progressed pretty early on durvalumab, but they’ve progressed pretty early from their chemoradiation. You’re not left with that many options in those patients. I’ll often try to rebiopsy, see if there's some sort of action with a mutation of some sort, maybe that’s not been done. As we said, we don’t always profile early stage patients. At that point, assuming a reasonable performance status, try to find some trial. Maybe it’s an I-O combination or an I-O plus chemotherapy combination. It depends what their toxicity profile is to the chemotherapy, the radiation, and the I-O.

How would you look at a patient on the opposite end of the spectrum, where they got the PACIFIC regimen, completed a year of treatment, and then 18 months later had evidence of disease progression? Would you look at that patient differently than the patients who progressed while they're receiving durvalumab?

That’s a tough one, but the answer is probably yes. They’re not prior refractory to durvalumab, although it could have been the chemoradiation effect. In a patient like that, the trials would have let them on, but I think in practice one could consider a rechallenge with immunotherapy, absolutely. Assuming there are no toxicities that would prohibit that.

Yes, I agree. When you start that late after the durvalumab, I think you start fresh as we would approach our typical stage IVs. You do full molecular profiling and NGS [next-generation sequencing], maybe rebiopsy to confirm this isn't some separate primary or another lung cancer, and if there are no driver alterations, I would challenge with immunotherapy-based treatment. Probably in that setting I’m more likely to go with some sort of combination, either dual checkpoint or chemoimmunotherapy.

One of the issues that we alluded to before, I think Stephen you said this, that the duration of a year of treatment was arbitrary. It is amazing to me that when we saw the 3-year overall survival curves that the difference was maintained despite getting that 1 year. Do you think there is opportunity, or we should think about longer duration because typically in stage IV disease we are wedded to this 2-year duration of treatment, and then wondering what to do at that point? Any thoughts? I’ll ask Roy to chime in on that too in terms of is there room for longer durations?

I think it’s a setting where you’re talking about generating a durable, immune-mediated, antitumor response. Ultimately, it’s not going to be a one-size-fits-all. I think there are going to be some people who need very little of the checkpoint inhibitor to induce T-cell memory, and some who may need more constant. I’ve had some very late relapses, for example, in small cell that I wouldn’t necessarily expect in a lot of my non–small cell cases. We've seen a lot of data, some presented by Dr Herbst, that showed when you stop after 2 years you can rechallenge with some success, but I think ultimately, we’re still looking for patient-based biomarkers that are going to help guide us. I am comfortable stopping and watching closely, but I’ll tell you that some of my patients are not comfortable stopping.

It can go both ways. I’ve had people who have gotten 2 or 3 doses of immunotherapy. They come off from toxicity, and we’re managing their toxicity with steroids for years, but their cancer never recurs. Then, there are some where we treat to progression, oftentimes in those cases, patients will say, “I’ve had enough.” Now, the intervals are stretching out. Six weeks now with pembrolizumab, and so forth, so it’s easier to do maintenance.

I like the 2-year mark as we heard from Stephen. That came out of KEYNOTE-010. We looked at those patients who had PR [partial response] or response in the [

] paper from earlier this year, and very few of them relapsed after 2 years of treatment if they were in that group. And when they did, about half of them responded again. A similar analysis is going on now for KEYNOTE-024, so we’ll see that soon as well.

Again, I think it’s each patient individualized, and in the absence of measuring memory T cells and knowing what's going on, it’s a bit empirical, obviously.

Videos

Treating for Stage III NSCLC After Progression on Durvalumab

Do you stretch the performance status [PS] rules? Obviously, PACIFIC was PS0 to PS1, but pretty positive results. Do you think those can be extrapolated to the poor performance status population, or what would you consider as a standard of care in a PS2, or dare I say, PS2.5?

I probably do stretch it a bit. Part of it depends on why the performance status is low, and chemoradiation is a tough treatment. I think it’s not unusual to have patients who are pretty tired, pretty weak from that therapy. And the first thing I do is try to wait, try to give them a little time to recover, maybe IV [intravenous] hydration, focus on nutrition and see if we can get some of that performance status back.

I’m balancing the potential improvement in outcomes with the toxicity, and durvalumab monotherapy in this consolidation setting is pretty well tolerated. I found it pretty easy to deliver, and I’m not really concerned that I’ll take someone who is PS2 and make them a lot sicker by delivering durvalumab. I suspect the outcomes are going to be worse than the PS0 to PS1, but I suspect the outcomes would be better in the PS2 compared to not giving it to them.

No, I agree. Few things have changed practice as rapidly as the PACIFIC results. The 2 papers back to back, first the PFS [progression-free survival]; we were using it based on the PFS, then OS [overall survival] came right on the tail, that’s such a good survival benefit. I try to give it everyone. We talk to everyone about it now at the beginning of the chemoradiation, so they're prepared for it. We try to give it as often as possible. Yes, I wouldn’t give it to someone who’s a PS3, but if someone is PS2, and you saw them a few times, and they're a PS2 and not a PS3, I’ve given it, and I think it does improve outcome.

I agree with what was said earlier, if you don’t get through a year, that’s OK. You do as much as you can, and when you stop you usually don’t retreat after that.

Kristin, your thoughts on the performance status issue.

For PS2/3 I think the hardest part of treatment is definitely the chemoradiation. For those patients, we are typically giving hypofractionated radiation alone, so it’s 60 gray in 15 fractions. And a case-by-case basis, if we think they can tolerate durvalumab, we occasionally will do sequential chemotherapy followed by radiation. I think there is an AstraZeneca trial underway that’s testing sequential chemoradiation followed by durvalumab for poor performers. Again, I think it’s the chemoradiation piece they struggle with, and we haven't seen very many new therapies for the PS2/3 patient. So I think it’s important to mount a trial that tests immunotherapy for that patient population.

One of the things that I think was reassuring about the PACIFIC trial is this issue of pneumonitis, that there didn’t seem to be an excessive amount of pneumonitis. Of course, one of the things we don’t know is the radiation parameters for the patients who were treated on both arms. Give us your perspective as a radiation oncologist, the issues around immune- mediated pneumonitis, radiation-mediated pneumonitis.

If you look at the contemporary chemoradiation trials, for example, R2GO617, the rate of grade 3 or higher radiation pneumonitis was about 6% or 7%. It’s gotten so much lower over the years because of improved technology. We can handle these bigger tumors. If we see changes on imaging that are within a treated radiation field, and the patient is symptomatic with increasing hypoxia, then we think this is likely due to the radiation. If imaging findings tend to be more widespread throughout the lung, I tend to think that would be more of an immunotherapy-driven pneumonitis. Sometimes it can be difficult to differentiate. We still don’t have any great biomarkers for this toxicity. I think it’s something that people worried about at the onset of chemoradiation followed by immunotherapy in stage III disease. But clinically it doesn’t happen that often, and I think that the oncology community is getting more comfortable with managing these toxicities, and our patients do overall pretty well.

I think in the PACIFIC trial they topped the radiation dose up at 66 gray. Is that correct?

The PACIFIC trial patients enrolled after they finished radiation, so the radiation dose wasn’t specified. You had to get at least 54 gray, so everybody got at least 54 gray, but there wasn’t a stopping point in terms of where everybody stopped. It was sort of dealer’s choice. If you look at PACIFIC-2 that’s enrolling internationally, patients obviously are getting just 60 gray, so the radiation parameters will be controlled for.

I would say the standard is 60 gray, based on R2GO617. Certainly, you can get better doses to your lungs with 60 gray as opposed to 66 or 70 gray. I never push it over 60 gray for non–small cell lung cancer.

I guess you would conclude that from the R2GO617 trial, but I still see our radiation oncologist going to 66, 70 gray. That’s probably based on volumes, but I was wondering if there's an accepted standard in the radiation oncology community.

Durvalumab in Stage III NSCLC Based on Performance Status

Let’s transition to one of the more influential trials. It’s been so wonderful to be a lung cancer doctor in the last decade and certainly recently. Someone pointed out we had 6 or 7 approvals in lung cancer over the last couple of months. It’s been a land of plenty and probably more to come as we’ll talk about. One of the more influential trials, and I want to ask Dr Liu his perspective on this, is the PACIFIC trial. We had reached a plateau in terms of what we could achieve for cure rates and survival in the concurrent chemoradiotherapy world. We saw PACIFIC come along and change the standard of care. Give us your perspective on that, and then do you think it’s been adopted at the community level? Are most people doing it and that sort of thing?

I think it’s been widely adopted because this is what we’ve been waiting for, for so long. As a reminder, the PACIFIC trial was a randomized phase 3 trial for patients with unresectable stage III non–small cell lung cancer. Patients received definitive chemoradiation with platinum-based chemotherapy delivered concurrently, and after completing treatment, in the absence of progression, they were randomized to receive durvalumab or placebo for 1 year. What we saw initially was a pretty profound improvement in PFS [progression-free survival], and at the [World Conference on Lung Cancer] in 2018 we saw that did translate to an OS [overall survival] benefit. The hazard ratio at that point was 0.52 for PFS, 0.68 for survival.

What we saw in the past year was more maturity, and with more follow-up we saw that survival benefit persist. We don’t see a dropping of that tail, that hazard ratio 0.69, a consistent benefit with delivery of durvalumab. We saw a median survival of 29 months with placebo, not reached with durvalumab, but the 3-year survival rate was 57%, and I think it’s been embraced by all of us. This is a space where we deliver a fairly toxic treatment. Chemoradiation is one of the tougher treatments that I have to coach patients through. The hope with that treatment is to deliver a cure. We know that for the majority of patients we don’t achieve that. The addition of immunotherapy [I/O] consolidation gives patients the potential for long-term benefit, long-term survival, and I think at first there was some concern about safety. I think that’s largely been quelled. It’s a safe drug to give; we don’t see very high rates of pneumonitis. There were some who were reluctant to get rid of consolidation chemotherapy. Maybe some on this call right now, and who instead are maybe giving that as induction therapy. Now, we’re very comfortable using durvalumab, and it’s become a clear standard.

In the trial design of PACIFIC, we had 26 doses or a year of treatment. At least some recent market figures suggest that the average patient doesn’t get nearly a year of treatment. How important is that to you to think you’ve got to push them through and get the full year in?

It’s 1 year, which is a nice, round number. That means it’s pretty arbitrary. At that 2018 update, if we look at the 473 patients who received durvalumab, only about 232 completed all 12 months. Some of the patients will drop off for progression, notably less than the placebo arm, and some patients will stop due to toxicity. Those patients may still derive benefit from durvalumab, but just may not need to continue therapy. My general approach is to go for a year, but certainly in the face of toxicity, if I coach patients through, the toxicity resolves, I’m unlikely to rechallenge someone because it may not be critical to finish that year.

Roy, any reason to check PD-L1 status in the consideration in this setting?

We do, but normally that will be the PD-L1 at the diagnosis and not after the chemoradiation, so all bets are off to what's going on in the tumor microenvironment. We tend to use it on patients regardless of PD-L1 status. There were some data I think early on that suggested lesser effects in low PD-L1. We’re pretty much using it in all groups.

We’ll eventually get to the ADAURA trial in this discussion, but that’s certainly going to push more frequent molecular testing in early stage disease. Right now, we don’t have a defined reason to do molecular testing in stage III, but it’s often done so you know that people may have a driver. Does that influence your use of immunotherapy after chemoradiotherapy, given the questionable data we have for instance in a patient with an 

Yes, it might, although if you look at the PACIFIC trial, there were a reasonable number of patients, under 10% or so….

 mutations, and that subgroup, albeit small, did well. I wouldn’t avoid it, but I think we’re moving toward a new trial where we’ll probably molecularly profile stage III patients. And then based on the results of ADAURA, there’s a trial called LAURA, and LAURA is going to be using osimertinib in that stage III chemoradiation post setting. I think that might be a very nice thing to do as well. Same concerns, the worry about ILD [interstitial lung disease] and other issues, and the effect of an EGFR inhibitor plus an I-O agent. Working out some of those timings, I think that would be a very nice thing to study in the future.

It changed practice, and I agree with you Dr Liu, I think people are enthusiastic about it. Everyone loves immunotherapy nowadays.

PACIFIC Trial: Durvalumab Following Chemotherapy for Stage III NSCLC

: “Multidisciplinary Management of Locoregional Non–Small Cell Lung Cancer.”

I’m Dr Mark Socinski from the AdventHealth Cancer Institute in Orlando, Florida. Joining me today in this virtual discussion are my colleagues, Dr Roy Herbst, a medical oncologist from the Yale Cancer Center in New Haven, Connecticut; Dr Stephen Liu, a medical oncologist from the Georgetown Lombardi Comprehensive Cancer Center of Georgetown in Washington, D.C.; Dr Kristin Higgins, a radiation oncologist at the Winship Cancer Institute of Emory University in Atlanta, Georgia; and lastly, Dr Brendon Stiles, a thoracic surgeon from the Weill Cornell Medical Center in New York.

Today we’re going to discuss a number of topics pertaining to the use of systemic therapy in patients with stage I through III non–small cell lung cancer. We’ll discuss the latest research in the field, including new data from the ASCO [American Society of Clinical Oncology] 2020 virtual meeting and the impact of recent clinical trials on making decisions around treatment selection.

Let’s get started on our first topic. In this population of patients, staging is a cornerstone of making decisions about future therapies. I wanted to ask Brendon to give us his thoughts, particularly on something that I think historically in the United States is often a shortcut in the work-up of patients, and that’s the adequate evaluation of the mediastinum in defining pathologic involvement of mediastinal lymph nodes and the various techniques we have to do the mediastinoscopy versus EBUS [endobronchial ultrasound] and those sorts of things. Give us your perspective on that mediastinal staging. Who needs mediastinal staging, what's the best way to do it? What are the pitfalls of EBUS, what are the pitfalls of mediastinoscopy? Start us off there.

You raised some great points Mark. I think we’re all excited to see both targeted therapy and immunotherapy moving into earlier-stage disease. But as you allude to, staging obviously becomes critical there and the sequencing of therapy, whether we even choose to include surgery as part of the therapy or whether we go to definitive chemoradiation, staging is critical for both resectable and unresectable patients.

I think the key point is as you hinted, staging needs to be done, and it’s probably best not just done with a PET [positron emission tomography] scan, but by invasive mediastinal staging. This is generally a population that’s getting considered for these trials because they’re thought to have positive lymph nodes, either N1 or N2 nodes. We know that if they have N1 nodes, they might have N2 nodes; if they have N2 nodes, they might have N3 nodes. I think it’s inherent upon us to stage well and to stage multiple stations. I think that can be done well by lots of folks, whether it’s a thoracic surgeon or a skilled pulmonologist.

I see EBUS and mediastinoscopy largely as interchangeable. I think the key is doing something. Certainly, EBUS has gained favor, it’s easier on the patients, it doesn’t require an incision, and in many studies, its actually more accurate. I tend to believe that particularly when you’re looking for PET-positive nodes and going right to the nodes that you’re suspicious for, you can get there well with EBUS, you can do multiple samples, and the yield is very high. I think the one thing that’s interesting, where we’ve moved toward EBUS and largely away from mediastinoscopy, I think the incidental N-positive stuff, whether it’s incidental N2 or N3, we’re not probably finding as much. If you see a patient with bulky N2 disease, in the old days we’d stick a mediastinoscopy down, and by default you’d get some N3 from the other side just in small nodes.

With EBUS the tendency is a little bit more to guide yourself toward just the big nodes, and the smaller nodes that you think are perhaps not positive are a little bit more challenging. That can have some significant implications for the patients though, as from being IIIA to IIIB or IIIC. I’m in favor of making sure that we sample both sides, trying to narrow down the nodal involvement and to come up with an accurate stage.

Then it’s just as important to do intraoperatively mediastinal staging. Could you comment on that?

That’s really key, and as we talk about adjuvant trials and I’m sure as Roy will talk about his trial, understanding which patients benefit is going to be key on doing good surgical staging during the operation. And there's a big difference between calling a patient stage I and taking 1 or 2 lymph nodes out, and calling a patient stage I and having sampled 31 nodes. Increasingly as we understand that we have agents that might be beneficial in the adjuvant setting, that idea of staging them well surgically, making sure that we get a lot of N1 nodes and N2 nodes so that we can be accurate there is critical, and probably has some implications for disease recurrence as well.

Then this issue, the term is so cemented in our lung cancer culture, this term unresectable stage III. Does unresectable mean you can’t resect it, or does it mean you shouldn’t resect it? Give us your perspective on that.

I think the latter is true. I always say that resectability, like beauty, is in the eye of the beholder. I think that anything can be resected. The question is really should we resect it? We know that there's probably some that we shouldn’t, and I tend to think of that as bulky multistation N2 disease. Certainly, that’s going to act more the equivalent of systemic disease, but even more importantly, I pause when I know that I’m going to have to go down the pneumonectomy road with one of these patients with a high burden of disease. I think that inflicts almost a second disease upon patients, and I think it leads them down a long road where they're not going to tolerate systemic therapy and they're going to have a harder time on any of these trials that we’re talking about.

That said, have I done it and do I think it’s appropriate for some surgeons to do? Yes. In young patients with excellent performance status. In general, the data have suggested that pneumonectomy patients do worse.

If I can do a lobectomy, I might be a little bit more aggressive with a patient with multistation N2 disease. I think the real question is should it be resected? I think the challenge of that is that answer is probably different depending in where you are, your institution, your surgeon’s comfort levels.

Let me ask Kristin. At least in my mind, this is an extension of it, obviously as you get to the perimeter of the surgical ability to resect something, you get into bulky disease. And volume in radiotherapy is so important, and we know that the toxicities are not necessarily related to radiating the cancer, it’s what the normal tissue around the cancer gets. What are your thoughts on radiation issues as they relate to tumor volume?

 Stage III patients, the radiation technologies that we employ to treat these patients have evolved tremendously over the past couple of decades. In my mind, any stage III patient is treatable to a curative dose with radiation. We’re typically using IMRT [intensity-modulated radiation therapy] technique to treat patients who have bulky disease that have contralateral mediastinal nodes or mediastinal and hilar nodes, N3 nodes. But you can deliver 60 gray safely with these advanced technologies, and if you have dosimetrists and physicists experienced in planning radiation treatment plans for bulky disease, you can typically achieve your doses to your normal organs at risk such that you won’t hurt the patient. Part of that is expertise that you develop when you’re treating a high volume of patients with lung cancer. I think it could be delivered safely certainly also in community settings, and it's really changed what can be treated safely with radiation when it comes to stage III disease. I think almost every stage III patient can be treated safely with our latest and greatest technologies.

Mediastinal Staging in Non–Small Cell Lung Cancer

: Maybe it’s changing an extensive-stage disease. We do see on all these immunotherapy curves there’s a better tail on the curve and who knows what’s going there. In limited-stage disease, this is on our list of potentially curable diseases with aggressive chemo/radiotherapy. This is a situation where I routinely use cisplatin/etoposide. There’s not much to say there from a medical oncology point of view. I’m a big fan of early intense radiotherapy, and I want Kristin to tell us what is early aggressive radiotherapy in this disease.

: Right now for radiation, we give 45 Gy bid [twice a day] with either the first or second cycle of platinum/etoposide. This was established as a standard of care by the Turrisi trial that was published in 1999, which confirmed what the CONVERT trial (that was published recently over the last 5 years) [showed]—the excellent contemporary radiation trial randomized patients to 45 bid or 66-Gy daily radiation with the hypothesis that the daily radiation to 66 Gy would be better. That did not end up being the case. There was no difference in overall survival between the 2 arms. Right now, people give either 45 Gy bid or 60 to 66 Gy daily. However, we did see an interesting trial presented at ASCO [American Society of Clinical Oncology], a small phase 2 Norwegian trial that was about 175 patients. They randomized patients to that standard 45 Gy bid compared with a dose-escalated bid radiation treatment course of 60 Gy twice daily. Their primary end point was 2-year overall survival and they did show significant survival difference: 73% versus 46%. This is a small phase 2 trial; we haven’t seen very much detail in regard to radiation technique. We don’t know much when it comes to local control, there wasn’t a difference in response rates between the arms. There’s also no difference in high-grade toxicity, which is puzzling. You would expect that with the dose-escalated radiation regimen you would get higher rates of esophagitis. I’m not sure what to make of that. I will say if you look at the control arm, it underperformed with median survival of just about 23 months. [In] the CONVERT trial, the 45-Gy bid median survival was about 30 months. I look forward to seeing this in publication so we can learn more details. I don’t think it’s practice-changing yet. It’s definitely interesting and I wouldn’t draw too many conclusions just until it’s tested in a larger phase 3 setting.

: It’s funny, I’ve always been a huge fan of the Turrisi trial, doing 45 Gy bid. It gets it done in 1 cycle and if you can start at day 1, by the time they get to cycle 2, they’re almost done with the radiation. They tend not to get their esophagitis until after the radiation is done so it all works out fairly well. How often is 45 Gy bid given?

: About 10% of patients get bid treatment. Logistically, it’s challenging. It’s difficult to schedule. Patients many times don’t like to come twice a day. In many radiation departments, it’s not in their routine to schedule somebody to come twice a day. For those reasons, for better or worse, it’s just not utilized as often as it probably should be. Even if it were positive in a large phase 3 trial, I still don’t know if it would replace 66 Gy given daily, which also gives great results.

: What are your views on PCI [prophylactic cranial irradiation] in a limited-stage setting?

: Right now, PCI is still standard of care in limited stage. It has shown to produce a survival benefit in meta-analyses; however, patients with limited-stage small-cell [lung cancer] are included in the SWOG MAVERICK trial, so we will be testing MRI surveillance in limited stage and I look forward to those results. It may be that perhaps we don’t need to do PCI if they’re getting q3 month MRIs. We don’t know that answer yet and I would hate to pull back on PCI in limited stage right now if the survival benefit in a patient population has the potential to be cured.

: We spent the majority of our first half of this thing talking about how immunotherapy has changed the standard of care in extensive-stage disease. Let’s get Steve and Roy’s opinion on limited-stage disease.

: I think that will be a big impact in the United States. There’s plenty of rationale to combine immunotherapy on the cusp of radiation. We learned in non–small cell from the PACIFIC study that there’s a potential synergy between them and that’s where we saw an improvement, not just in PFS [progression-free survival] but in overall survival, we now accept checkpoint inhibitors after thoracic radiation. Years ago early on, we had some concerns about the possible risk of pneumonitis. We didn’t know if it would be higher using immunotherapy after thoracic radiation but now, we’re very comfortable with that—the safety of that approach clearly established. Based on the rationale for potential synergy, once we start introducing checkpoint inhibitors in the limited-stage setting, hopefully we’ll see more cures. Our goal in limited-stage small cell with chemo and radiation is to cure patients, but we know that for the majority of patients, we don’t achieve that goal. Hopefully, use of checkpoint inhibitors will allow us to do that, and there are a couple of very important studies.

One of those studies is chaired by Dr Higgins and that’s using atezolizumab. Dr Steven Lin at MD Anderson did a small phase 2 [study] looking at concurrent thoracic radiation in non–small cell [lung cancer] with atezo [atezolizumab]—so radiation of the chest and atezo at the same time just to be sure there weren’t any worrisome signals in terms of pneumonitis. The rate of grade 3 pneumonitis was quite low, about 3%. Immunotherapy can [cause] modulation [in] the microenvironment and facilitate the efficacy or radiation and vice versa. This study is looking at atezolizumab with chemoradiation followed by atezolizumab maintenance afterward. Kristin, correct me, I think it’s NRG LU005.

: That’s currently enrolling, so we’re trying to send patients over to that study.

: Yes, we have just about 100 patients on so far.

: Roy, what about immuno combos in this setting? What do we know about the ADRIATIC trial?

: The ADRIATIC trial is looking at chemoradiation followed by durvalumab, and that’s certainly an approach. We’ve always been taught to use these drugs after and then to add tremelimumab. There's less enthusiasm for that right now given the results of that arm of the CASPIAN trial. These are curable patients; you want to watch out for the toxicity. The trial is ongoing, so it’s another setting. Perhaps in this setting, you can deliver the tremelimumab better, maybe it has a different effect after getting radiation but we’re not that optimistic given what we’ve already seen with CASPIAN trial.

: Yes, but certainly the concept building on the PACIFIC trial in non–small cell makes sense for the monotherapy arm.

: Yes, you can argue for that the effect of immunotherapy in a tumor that’s received chemotherapy and radiation therapy. You can almost imagine it would be nice to go study, but I think you’re warming up the whole microenvironment and making it ready for immunotherapy. As Stephen said, the toxicity of this is always a concern, but it looks like it’s quite manageable.

: Are there any parting thoughts to our audience in the general field of small cell? What’s the message you want? I’ll start with Kristin as our lone radiation oncologist.

: I’m excited that we have new therapies for patients with small-cell lung cancer. Immunotherapy has shown small but consistent survival benefits for our extensive-stage disease, and I’m excited about the prospects of moving that into limited-stage disease and curing more patients with small-cell [lung cancer].

: Although there are encouraging combinations looking at different immunomodulators, TIGIT for example, I think the only path forward to get those hazard ratios we’re used to in non–small cell [lung cancer] is with some type of reliable biomarker. We’ve done a lot of work looking at sequencing, looking at PD-L1, TMB [tumor mutational burden], there are just no obvious answers there. The greatest lead has to do with those transcriptional factor subsets looking at ASCL1, narrow D1, 

, maybe as a predictor for I-O [immune-oncology]. Without a biomarker, it’s only going to be incremental gains.

: We’re making progress. We’ve built on platinum, but I’d say we haven't made it all the way. I agree with the others that we need biomarkers, but as long as you’re having some activity, biomarkers become very viable because you can hopefully build on what we’re seeing. I think there’s so much more enthusiasm in the study of small cell than ever before. There are meetings on small cell alone. You recall Mark, the targeted therapies meeting we have every year, we always put small cell as the last session on Saturday. This year, we opened up with it. More investigators, more new ideas, and patients with this disease are benefitting from that. That’s a very positive thing.

: Thank you all. It’s been great. It’s been a great discussion. Hopefully, this will be helpful to our audience, and thanks for joining me today for this discussion on perspectives in small cell.

Review of Treatment for Limited-Stage Small-Cell Lung Cancer

: The same time that we had these data, we also had third-line indication for immuno-monotherapy in this disease setting, and I wanted to get the perspective. Dr Liu, clinically, how many patients get to second-line [therapy]? How many patients get to third-line? It’s a tough population, but what’s your experience there?

: There’s a lot of attrition with small-cell lung cancer, much more than with other cancers. We have published data in this setting. If you look at a group of patients who received first-line treatment, the data will tell us about half would get second-line and less than a quarter would eventually get third-line [treatment]. The approvals of nivo [nivolumab] monotherapy [and] pembro [

 monotherapy in the third-line are important approvals. But for a potentially transformative drug, they would have much less impact because patients wouldn’t survive long enough to receive third-line treatment. That’s why the front-line treatment with atezo/durva [

durvalumab] has the chance to make a much bigger impact.

: What is your standard second-line [treatment] following first-line chemo-immunotherapy?

: It’s a setting where I look for a trial if we can. Trials are my preference. If I’m taking a board exam, my answer is topotecan, but if I’m in practice, that’s a drug that I’m disappointed with. I find it very toxic; quality of life is not so great with topotecan. It’s a tough drug to receive and the responses are fairly limited. There are many other agents that are equally good or bad. Taxanes, irinotecan, temozolomide, if there’s CNS [central nervous system] efficacy. It’s an area where we have an unmet need for more potent agents.

:No. Topotecan—I hate using it. I have. We sometimes use taxanes here, but that’s where we send them over to phase 1. I still remember a patient I sent over to phase 1 years ago for an immunotherapy who is alive 7, 8 years later. Now, we’re in the post–I-O [immune-oncology] world. I think we look at I-O combinations if a patient is strong enough. Some of the ADCs [antibody drug conjugates], I think are worth exploring there, but it’s a tough area. At least, we’ve elevated from where we were in the past [by] having immunotherapy to begin with.

: We are seeing patients that get a fair durability to their responses on immuno-maintenance therapy. Is there a cut point in which you would think about going back or adding platinum/etoposide back in at some point?

: In the absence of data, it’s hard to say. If someone becomes resistant, add back some chemotherapy, and if chemotherapy is helping in the first place, probably knocking down some immune-resistant cells or regenerating some neoantigen [is a good idea]. It’s something to try and if someone is not having any issues with clinical progression, or if they’re just progressing radiographically, it’s worth a try.

: Any role for nivo/ipi [ipilimumab] in the refractory setting following first-line I-O? You mentioned I-O combinations earlier.

: We’ve done that and we’ve had trials. I’m a little disheartened in the fact that durvalumab/tremelimumab didn’t seem to have any effect up front because it’s a different situation. But nivo/ipi has phase 2 experiences, but you’re just giving the patient a lot of toxicity and the absence of any real data; I’ve not used it that much.

: I haven’t used it but the data look interesting. Lurbinectedin is a transcription inhibitor; it binds onto the DNA promotor region that prevents transcription. It also has an effect on tumor-associated macrophages, which may alter the microenvironment and help facilitate some immune responses. In a single- arm study of over 100 patients, it gave a response of about 35%. In [patients who were] platinum sensitive, that was up to 45%, and in [those who were] platinum resistant, 22%. It’s impressive for [patients who are] platinum resistant. We don’t have any drugs that are active in that setting. We’re waiting for the randomized data. We need a control arm there, and the ATLANTIC trial is looking at lurbinectedin with doxorubicin versus topotecan or CAV [cyclophosphamide, doxorubicin, and vincristine], and I think when we see those data, we’ll know more about just how active this drug is, but there is promise in that area.

: I would agree. When those data were presented at ASCO [American Society of Clinical Oncology], it was almost too good to be true; we were all very impressed and we’re waiting for the randomized trials. That could have a real mixture especially given our current paradigm using immunotherapy up front.

: Any appetite for PARP inhibition in this setting? There’s been some work, although I must say the data that I’ve seen have had a modest impact in this disease setting from my perspective. I don’t know if either of you have a different feeling.

: I find them exciting. When we think of PARP inhibitors throughout oncology, we often think of tumors that have defects and BRCA or a homologous repair, but these drugs also have some activity in small-cell [lung cancer]. Monotherapy didn’t really get us there. We remember the STOMP trial looking at maintenance PARP that didn’t really show much activity. I think there’s a lot more promise in combinations. It makes sense to combine a PARP inhibitor with a drug that will induce single-strand DNA breaks. Olaparib is a bit of a stronger PARP trapper than veliparib and in combinations with temozolomide for example, I think there’s some promising activity there. PARP inhibitors have more promise and maybe in combination with immunotherapy. We know from work that our colleagues have done that inhibition of PARP using PARP inhibitors, using CHK1 [checkpoint kinase 1] inhibitors will drive up PD-L1 expression and will induce T-cell infiltration. A CHK1 inhibitor will have an antitumor effect in small-cell lung cancer models, but if you deprive that model of CD8-positive T cells, it has no effect showing that its efficacy is medicated through the immune system.

Second- and Third-Line Treatment for ES-SCLC

: Kristin, I want to get your opinion. In the design of these trials we continue immunotherapy as maintenance. The 2 questions we used to address when we used to give 4 to 6 cycles of platinum/etoposide was A) is there a role for PCI [prophylactic cranial irradiation] in extensive stage disease, and B) is there any role for thoracic radiotherapy in this setting? I’m going to ask you that question first, and then if there are selected patients for which you would consider either, how do you integrate that when you’re giving maintenance immunotherapy?

: That’s a great question. Radiation oncologists now are wondering how PCI and consolidated thoracic radiation fit in with the results of the CASPIAN and IMpower133 trials. For PCI in the extensive stage setting, radiation oncologists have stopped recommending it due to the conflicting data. The trial led by [Ben] Slotman, [MD, PhD,] and the Japanese trial showed opposite results with improved survival with PCI given in patients who don’t get routine MRIs of the brain. The Japanese trial showed that there was not a survival benefit if we give surveillance to patients with extensive stage small cell lung cancer with q3 [every 3] month MRI. We’ve seen a shift in radiation oncology with not recommending PCI in patients with extensive stage small cell [lung cancer].

In IMpower133 only about 10% of patients received PCI, and in the CASPIAN trial PCI was allowed on the control arm, but not the experimental arm. We didn’t see any worrisome toxicity in the patients who did receive PCI in the Impower133 trial. But with PCI there is significant toxicity, and as a field, we’re trying to potentially move away from PCI. There are more trials now addressing MR [magnetic resonance] surveillance in both the limited stage and the extensive stage small cell population. The SWOG cooperative group is running the MAVERICK trial, for example, that will help answer this question. When patients do get PCI in extensive stage, there's also a trial run through NRG [Oncology], CC003, which is giving PCI with hippocampal sparing, which carves out the part of the brain that is responsible for creating memories to try to reduce cognitive changes. So as a field, we’re leaning away from PCI in this patient population and that’s where we stand now. I hope the SWOG trial gets completed. I think it’s a great trial, and I would encourage people to enroll patients to answer this question when it comes to PCI.

In terms of consolidated radiation, patients weren't allowed to get thoracic radiation on either of these trials. We do know now we have some safety data for the combination of thoracic radiation and immune checkpoint inhibitors, and there's not worrisome toxicity. The role of consolidation radiation to the chest and to metastatic sites is going to be evaluated in an NRG trial, NRG-LU007, which will activate probably late summer. I look forward to putting patients on that trial. Right now, I would say we’re giving thoracic radiation on a case-by-case basis in some patients who have had a great response and have a small amount of residual disease. We’re doing so cautiously, because again, there are a lot of unanswered questions. What dose do we go to? How do you integrate it from a timing standpoint? And this is a data-free zone. I think we’re best to put patients on NRG-LU007 to answer the question in a scientific way.

: There was a suggestion from a very old trial published in the late 1990s, an Eastern European trial, that suggested in those patients who have a great response, maybe you could get some mileage out of thoracic radiotherapy, and as well with the follow-up Slotman trial. Still controversial, we still think about it and talk about it, but I’m glad you’re doing NRG-LU007 to help bring some more clarity to it.

Role of PCI Versus Brain MRI Surveillance in ES-SCLC

: Roy and Stephen, what do you do in your own practice? Do you have a preferred agent?

: Atezolizumab was there first, and all else being equal, the drug there first usually gets more share. We’re using mostly atezolizumab now. I didn’t see anything in the data to switch. I will say the pembrolizumab data look very close. What it tells me is that we need a better biomarker here. The fact that all these trials are so close, it tells you that we have a population that’s heterogeneous, and some are probably benefitting more than others, and if you take a mixed population, you're going to see results like this. It’s great for patients, it’s clearly better than what we were using before, but we’re using atezolizumab at Yale [Cancer Center].

: It comes down to comfort. IMpower133 was presented in 2018, which was approved March 2019. Durvalumab was approved in March 2020. I think what might have changed it, if we had seen the third arm in CASPIAN, the tremelimumab arm, showing any benefit in survival, then that would have been a combination to pursue. But as you saw at ASCO [the American Society of Clinical Oncology annual meeting], the addition of tremelimumab did not improve survival over just chemotherapy alone. [Atezolizumab] and [durvalumab] both improve survival, And both are reasonable options. I didn’t see a compelling reason to change. CASPIAN, [durvalumab] is given every 4 weeks. We also have FDA approval for [atezolizumab] to give every 4 weeks. It comes down to comfort for me, and I’m still using atezolizumab.

: Roy, you mentioned we did see at ASCO the third arm of the CASPIAN trial, which was the durvalumab/tremelimumab arm. The interesting thing to me is that there didn’t seem to be any optimism about that combination, and I think the tremelimumab was stopped at a certain point. And the overall survival curve with continuing durvalumab alone eventually caught up with the arm that had only durvalumab in it. Roy, what are your thoughts, any hope for anti–CTLA-4 inhibition in this setting?

: I would say not. We already knew from trials with ipilimumab years ago, our colleague ran some of those trials way back when, that there was no real benefit with ipilimumab CTLA-4. And here, adding durvalumab clearly adds toxicity, but unfortunately, no benefit, as you mentioned. I think if there are going to be combinations in small cell lung cancer—and there have to be, because these data, while good, are clearly not a home run yet—we’re going to have to look at other aspects of the immune system and try to scientifically understand why there is some primary resistance to these agents. For now, I would stay away from the CTLA-4 inhibitors. That brings the grade ¾ toxicity up to the 40%-plus range, which is high in these very sick patients.

: Roy, you brought up before the issue of biomarkers. Obviously, in non–small cell [lung cancer], we routinely measure PD-L1. Any role for that in small cell?

: I think yes. The problem is with PD-L1 both in small and non–small, Mark, is measuring it accurately. It’s hard enough to measure in non–small cell where you get good pieces of tissue and there isn't crush artifact, and so forth. In small cell it’s hard to get good core biopsies and really measure it accurately. I think it’s a measurement issue, but I think PD-L1 probably has some role but we've not seen it so far. TMB [tumor mutational burden] could certainly be useful. There are a lot of data recently emerging with whole exome TMB, looking at 175 mutations per megabase in some of the data with pembrolizumab. I wonder if that could someday be used with small cell. All these need to be incorporated in the trials. Perhaps all of the groups that have done these trials could collaborate and pool their data sets to look at this.

Expert Approaches to Treating Extensive Stage SCLC

: With both of those being anti–PD-L1 antibodies, I’m going to ask Dr Liu, we are coming off the tail of our first virtual ASCO [the American Society of Clinical Oncology annual] meeting this year. And at that meeting we saw the presentation of 2 trials with PD-1 inhibitors, KEYNOTE-604 with pembrolizumab, and the ECOG-ACRIN 5161 trial, which was actually a phase 2 trial with nivolumab. Can you walk us through those and give us your impressions?

: Yes. These are 2 randomized studies and we saw results for the first time. The phase 3 trial you mentioned, KEYNOTE-604, was presented by Charles Rudin, [MD]. This was a very well-designed randomized, placebo-controlled large phase 3 trial. It included patients with previously untreated stage IV small cell lung cancer. All patients received platinum/etoposide, allowed either carboplatin or cisplatin, with a 1:1 randomization to concurrent pembrolizumab or placebo, followed by maintenance [pembrolizumab] or placebo. The study had 453 patients, of note, the vast majority, about 70%, received carboplatin. And it had dual primary end points of progression-free survival [PFS] and overall survival [OS]. What we saw at ASCO 2020 was the final analysis, and in that analysis KEYNOTE-604 was positive in that it hit its progression-free survival end point. The PFS favored pembrolizumab a median of 4.8 from 4.3 [months], the hazard ratio there was 0.73, the 1-year PFS rate from 5% with placebo to 15% with [pembrolizumab].

Unfortunately, overall survival did not cross the threshold for superiority. There was a numeric difference, median from 9.7 to 10.8 [months], hazard ratio of 0.80, but it did not cross that statistical threshold for a positive OS benefit. It’s interesting, if you take away 1 patient who inadvertently received the wrong treatment, it was a positive trial, just to show how close it was. We learned from KEYNOTE-604 there is activity there, comparable, in the same ballpark, as we saw with PD-L1 in IMpower133 for atezolizumab, and in CASPIAN for durvalumab. But unfortunately, this will not impact practice because it did not improve survival; while the trend was encouraging, it didn’t quite get there.

The ECOG-ACRIN 5161 was a randomized phase 2, through the cooperative group. It accrued remarkably fast, and this study looked at platinum/etoposide with or without nivolumab. No placebo, choice of platinum, this was a smaller study, a phase 2, 160 patients, and this study accrued in 7 months. Primary end point was progression-free survival, and that improved with nivolumab from 4.7 to 5.5 [months]. It’s a hazard ratio of 0.68. Even though a relatively modest size study, it was able to show a PFS benefit and was able to show a survival benefit. The OS hazard ratio there was 0.73. This was a smaller phase 2 positive for both PFS and OS. In a world where we have multiple randomized phase 3 trials showing an OS benefit with atezolizumab, durvalumab, unfortunately, no immediate impact in our clinic.

KEYNOTE-604 and ECOG-ACRIN 5161 Trials for ES-SCLC

: I’m Dr Mark Socinski from the AdventHealth Cancer Institute in Orlando, Florida. Joining me today in this virtual discussion are my colleagues, Dr Roy Herbst, a medical oncologist from the Yale Cancer Center in New Haven, Connecticut; Dr Stephen Liu, a medical oncologist from the Georgetown Lombardi Comprehensive Cancer Center of Georgetown [University] in Washington, DC; and Dr Kristin Higgins, a radiation oncologist at the Winship Cancer Institute of Emory University in Atlanta, Georgia. Today we’re discussing a number of topics pertaining to the use of systemic therapy in patients with small cell lung cancer. We’ll discuss the latest research in the field and the impact of recent clinical trials on making decisions for treatment selection in this population. Dr Herbst will summarize recent trials because in the past year, we’ve seen a change in the standard of care based on 2 trials, IMpower133 and the CASPIAN trial. Could you bring us up to date and give us your impression of those trials?

 Yes. Immunotherapy has changed the way we think of cancer care, certainly lung cancer care, and it’s moved to small cell lung cancer. It makes sense. Small cell lung cancer is a smoking-related disease, there are large numbers of mutations, high TMB [tumor mutation burden], and it’s an obvious place to look for a new indication. The first drug to move forward was atezolizumab. At the World Conference on Lung Cancer 2 years ago in Toronto, the results were presented of IMpower133, which took atezolizumab plus platinum and etoposide in extensive stage small cell lung cancer. In my career, I haven't seen any changes in the standard of care treatment for small cell lung cancer until now. This randomized phase 3 study had a hazard ratio in the 0.7 range in favor of the atezolizumab, and that was approved and has become a new standard of care. Just right on the heels behind that is a second drug, durvalumab, another PD-L1 inhibitor, in combination with platinum/etoposide. The CASPIAN trial, which we learned about late last year, also was positive and updated at ASCO [the American Society of Clinical Oncology annual meeting] this year, again, with a hazard ratio between 0.7 and 0.8.

We have activity here; it’s a survival benefit. Its modest, but clearly, it’s at the level where we consider that clinically significant, and it’s something to build upon. For patients with small cell lung cancer, it’s great that we have these 2 drugs available in the frontline setting for this disease.

Roy S. Herbst, MD, PhD, Yale Cancer Center

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