 I’m David Spigel. I’m the chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee. I’m also a medical oncologist at Tennessee Oncology. And I lead our lung cancer research program. It’s my honor to be here to talk about stage III non–small cell lung cancer management and focus on the recent update of pivotal data on the use of immunotherapy in the treatment stage III disease.

A little about stage III lung cancer in terms of how we manage it. This used to be a medical school and fellowship, a topic folks stayed away from because it was so controversial. Basically, we’re trying to define whether someone has resectable cancer or is unresectable. In non–small cell lung cancer, that usually starts with CT and PET [positron emission tomography] imaging and an assessment of mediastinal disease. If we’ve ruled out distant disease, you’re trying to assess if somebody has mediastinal disease. Using the help of our navigational bronchoscopy tools with our pulmonologist, interventional pulmonologist, or interventional radiologist—or even our surgeons getting sample of the mediastinal nodes—is critical in confirming disease or not.

Once we know a patient has stage III disease, the question comes down to if they are resectable or not. Obviously that depends on your institution. But in general, we’re looking for minimal station or mediastinal disease. So low volume, single-stage disease. It’s very rare these days to take somebody with stage III cancer beyond 1 station or 1 lymph node to surgery, just because the outcomes have been poor in that group in patients with stage III disease. As I’ll show you, our patients do much better with chemoradiation followed by immunotherapy than they used to with just simply chemotherapy and radiation.

One last thing about stage III cancer. We try to get chemotherapy and radiation therapy for unresectable patients together. It’s not the end of the world if it’s sequential, but we try to get concurrent because that’s been proven to be better than sequential. I’ll come back to molecular testing, but right now, for unresectable stage III disease, molecular testing, PD-L1 testing—at least in the United States—really doesn’t have a bearing on your choice of therapy in terms of unresectable stage III disease, but maybe we can get into some of that in a little bit.

Everything changed really when PACIFIC was finished and results were made public. This is the pivotal randomized phase 3 trial looking at the role of immunotherapy, specifically the PD-L1 inhibitor durvalumab after standard chemoradiation. Remember the design of this study. This was looking at patients with unresectable stage III cancer. All patients were allowed to receive chemoradiation therapy according to institutional standards. And the randomization was after that, so up to 42 days after chemoradiation therapy ended, patients were randomized to durvalumab given at every-other-week schedule, so 10 mg/kg every other week for 1 year or placebo.

This was a placebo-controlled trial, and the study was designed to look at both overall survival and progression-free survival and then a variety of secondary end points we’ll get into. This study was already presented by Dr Scott Antonia and colleagues. We were fortunate to be a part of this trial at Sarah Cannon, and we’ve seen these results. They’ve been published in the 

 twice, first for progression-free and then for overall survival.

But most recently at ESMO [European Society for Medical Oncology Congress], we saw an update, specifically a 4-year overall survival update. That’s what’s been exciting. We had known obviously that durvalumab is superior to placebo following chemoradiation therapy and leads to a survival and progression-free survival advantage, but at ESMO we saw the 4-year update. The hazard ratio remains quite low, 0.71, so a 29% reduction of risk of dying for those patients on durvalumab vs placebo. What was most impressive, though, was the kind of landmark assessment. At 2 years, the overall survival was about 2 of 3 patients were alive on durvalumab compared with about 55%. At 3 years, it was about 57% vs about 44%.

As I mentioned, the purpose of this update was the 4-year overall survival analysis. What we know is that about 50% of patients were alive compared with about 36% of patients on just standard chemoradiation followed by a placebo—a substantial advantage. That alone was groundbreaking. This updated analysis gives us confidence that the initial results are holding true, that there’s a group of patients who continue to benefit and appear to be long-term survivors. More to come as the years pass. The numbers are still quite large. There are about 270 patients involved in the 4-year analysis, which isreally quite fantastic.

We also learned that progression-free survival was in favor still for durvalumab at 4 years. About 35% of patients were progression-free vs about 20%. That 20% number really hasn’t changed for 2 decades or so. We see that 35% of progression-free is really fantastic.

Understanding the PACIFIC Trial

 When we look at if there certain groups of patients who benefit over others, it really doesn’t pan out. In other words, everybody who has unresectable stage III cancer, whether it’s adeno or squamous—and I’ll get into this in a little more detail, but even if there are molecular findings, such as 

 mutations or PD-L1, we use PD-L1 expression—across the board everybody seemed to benefit. There’s not a gender or an age or, as I mentioned, a histology subset that does better or worse.

 in PD-L1 because this has got the most potential from PACIFIC recently since approval. Let’s talk about 

 first. To get on the study, it wasn’t a requirement to know the 

 of patients, so it wasn’t part of the primary design to say, “Well, patients are stratified for 

 mutation status.” As it turns out, there were very few patients with known 

 positivity. In fact, the numbers end up being about 24 vs 43 patients in terms of placebo, durvalumab exposed, placebo exposed when you look at the overall survival [OS] analysis.

 positive, in that limited sample, if you look at the wide confidence interval, it crosses 1 on the forest plot. What we know about that is that we don’t have enough information to say whether a patient benefits from durvalumab or not. Actually, if you look at the statistical analysis of the forest plot, the median of that confidence interval was to the left of 1, suggesting benefit for durvalumab. But because it crosses 1, all we can say is the confidence interval is wide and we don’t have enough patients. Now, because immunotherapy has not proven itself in 

-mutated patients, some controversy has come up about whether you should use durvalumab in patients with 

 mutations. And this is still a healthy debate.

Personally, I look at this trial as an intent-to-treat study. In other words, we treat all patients who went on this study as we would our patients we’d see in the community. Because 

 testing was not required for this trial, I don’t think it’s required in standard-of-care treatment. For my patients who have unresectable stage III, I don’t routinely test for 

. But if I did, if I did have that result, I still think durvalumab is the treatment for them because it’s proven to offer a survival advantage. And we don’t know with certainty that patients with 

 mutations would not benefit. I don’t want to withhold an opportunity for those patients.

Now, for PD-L1 expression, the same can really be said. PD-L1 expression was not a requirement for getting on the study. It was a post hoc analysis required by European regulatory authorities. In fact, in Europe, durvalumab cannot be used unless there is PD-L1 expression. That was probably an overreach of regulatory authorities because the study was not designed for that cutoff to be used in a primary analysis.

Here’s what we know. If you look at patients who have greater than 1% PD-L1 expression, in the forest plot the advantage for both PFS [progression-free survival] and OS is in favor of durvalumab. We say anybody who has expression on that analysis seem to benefit for durvalumab. If you look at the patients who are 0—and there were about 225 patients in total who would be scored as 0—the confidence interval crosses 1. If you look at the median of that confidence interval, it’s to the right of 1, suggesting that patients with no expression of PD-L1 do not benefit from durvalumab. That’s why European regulatory authorities do not allow durvalumab for those patients.

However, if you look at progression-free survival, the opposite could be said. That is, it crosses 1, but the benefit appears to be in favor of the 0s. This is like 

: We simply don’t know. With all the problems of PD-L1 testing, the heterogeneity and the tumor sample of testing and the tumor sample you have, and the uncertainties about this post hoc analysis, when you have a therapy that substantially affects 4-year overall survival, progression-free survival, I’m not going to deny a patient access to that because I have an IHC [immunohistochemistry] in front of me that says their PD-L1 is 0. I just don’t think that’s fair, and I don’t think there’s enough information there to deny a patient a chance of...

To that end, I think durvalumab is the standard of care for patients with unresectable stage III cancer after chemoradiation. It’s given for 1 year. Is that enough? Is that too much? We don’t know. That’s just how that study was designed.

The Role of Molecular Testing in Lung Cancer

 I want to focus a little on the safety of immunotherapy in stage III cancer. In stage III cancer, the treatment plan can be a bit complicated when you go through this with patients at the beginning because it has so many different elements. We’re first talking about the stage of cancer, and that you don’t think surgery is the right kind of modality to use in their care. You’re thinking about your chemotherapy regimen in radiation therapy. Remember, in PACIFIC, any platinum-based chemotherapy doublet is considered reasonable. I use carboplatin-paclitaxel routinely. There is not a role for induction or consolidation chemotherapy in that trial. It was not something that was administered. Then transition to immunotherapy. There are a lot of elements here in terms of how you do all those.

Remember, pneumonitis is probably our No. 1 toxicity, along with esophagitis and mucositis. They come about from chemoradiation therapy, so that transition from the end of chemoradiation to the beginning of immunotherapy, for me it is predicated on how the patient is doing from a pneumonitis perspective and esophagitis. Because we want to be through that before we introduce something that could also cause that. We know the rate of severe pneumonitis was below 5%, probably closer to 3% with durvalumab in the PACIFIC study. But we know pneumonitis anyway, even all-grade pneumonitis, is relatively common with chemoradiation therapy. I try to make that assessment. I use imaging to get an assessment of how someone’s lungs look, how they’re feeling obviously...before we embark on...

As you go through a year with immunotherapy, remember you have all the things that can happen with immunotherapy, your flare with stage IV setting. We’re still watching for those toxicities—any of the inflammatory conditions that can occur with the colon, with the thyroid gland, with the kidneys, with the liver, and the pancreatitis, so all the usual assessments you’re doing in general. In my experience, if you get through that first transition period from chemoradiation to immunotherapy in a way where the patient doesn’t have any setbacks and there doesn’t seem to be an exacerbation of their pulmonary..., getting through the next year tends to be pretty straightforward.

When you have difficulty in those first 2 or 3 months in terms of starts and stops—using steroids and antibiotics for what you perceive to be bronchitis, possibly pneumonia—it does get hard to get people back on consistently and stay through that. Sometimes you do have to use steroids routinely to keep them off therapy for a year. But usually you know all this in the beginning. I think for the minority of patients who have not been able to get through a year of durvalumab, we figure that out pretty early on. Largely it was because of.... I tend to image patients about every 3 months with unresectable stage III disease. Once we start durvalumab, that’s the plan of care. Of course, if patients do well long term, I reduce the frequency of those evaluations.

I think 1 year is the standard simply because that’s the way the study was designed. You’ll see emerging data coming out from some ongoing trials. Look at that question a little differently. There are some studies designed to stop at a year, and some just keep immunotherapy going. That’s a strategy I’m hoping doesn’t become a new standard because for stage III cancer, you’re trying to cure somebody to have start-and-stop therapy and not have them be on that forever. Indefinite immunotherapy sounds more like treating stage IV cancer, but that’s really not what we’re trying to do here. We’ll see what those trials show. But in the PACIFIC study, what’s FDA approved is 1 year. We try to stick with that.

Toxicities Seen in the Treatment of Lung Cancer

 What about somebody who’s not as fit, has a poor performance status, or is perhaps older, and you’re concerned about everything? That’s real life. That happens a lot. Not everybody has a performance status of 0 to 1. You approach this in the best way you can. I have recently had an older woman with poor performance status who simply couldn’t get through concurrent chemoradiation. In my mind, she was a candidate for sequential treatment and then still a candidate for when it happens for durvalumab.

The benefits for concurrent vs sequential are real but small. Sequential is not so bad. You should offer it to patients, or you can do sequential because it’s the right choice for that patient. That’s OK. Although PACIFIC was not designed for that—certainly the label does not include sequential use of treatment—that is how I treat my patients when I give them immunotherapy after sequential therapy if that’s the right way to treat them. Honestly, there are very few people I’ve given sequential therapy to, and it’s because performance status or advanced age are contraindications to concurrent therapy.

One controversial area I’ll bring up: What do you do with a patient who has stage III cancer that was resected? I’ll give you the take-home quickly. PACIFIC did not include those patients, and there is no role for immunotherapy in those patients. However, with all that said, there are patients who go to surgery for stage I or II disease, and then N2 disease is discovered at the time of surgery. The patient is treated and closed up. They go through surgery, but they have bona fide stage III cancer. You say to yourself, “Gosh, had I known that in the beginning.” Hopefully that patient was evaluated in the mediastinum but it was just passed over. I might not have sent that patient to surgery, and I would have treated them with chemoradiation and durvalumab. So here’s a patient in front of you now who just got surgery for stage III cancer. Well, that patient now gets adjuvant chemotherapy.

Not a topic for this section, but some recent data from ESMO [European Society for Medical Oncology Congress] actually advised against postoperative radiation therapy…. Again, that’s a topic for another session. But that patient probably doesn’t get radiation anymore. Should that patient be offered durvalumab? The simple answer is no, that’s not standard. Is it wrong to have a conversation about it or even to use immunotherapy in that setting? I don’t think anything is wrong, but it’s not approved to be used that way. As long as you have a thorough conversation with your patient about what we know, what we don’t know, you’re doing right by your patient. It’s important to know what PACIFIC was and what it wasn’t. The pivotal neoadjuvant and adjuvant trials for resectable lung cancer with immunotherapy are here. Those will read out in the next couple of years, and we’ll know more about the role of immunotherapy in those patients.

Special Patient Circumstances and Immunotherapy

 There are ongoing trials in locally advanced lung cancer, both from the sponsor of PACIFIC, AstraZeneca, and other pharmaceutical biotech companies, looking at combinations with CTLA4 antibodies, administering checkpoint inhibitor therapy with radiation—not waiting for afterward, giving immunotherapies before chemoradiation therapy. A lot of these things are being examined in ongoing studies. I suspect the field will continue to evolve, but immunotherapy is here to stay in stage III cancer.

The other things that are on the horizon are obviously going to be other agents. But the idea that immunotherapy will find its way into resectable lung cancer, just as osimertinib is finding its way into resectable lung cancer. I think that could have implications for how you unresectable approach stage III cancer in the future. But for now, durvalumab is the standard of care. Other data look promising with pembrolizumab, and some early data we’ve seen from some combinations look promising. But nothing is certain in the United States.

Probably the 1 that keeps coming up has been largely around 

 and PD-L1 testing, and we’ve spent some time discussing that. I don’t think it’s going to stay this way. There will be emerging data that teach us more about the role of immunotherapy in patients who don’t express PD-L1, patients who have 

...mutations. But I do believe that for patients who meet the criteria for enrollment on that study, which is pretty much everybody with unresectable stage III disease.

Immunotherapy in Non–Small Cell Lung Cancer

Data from the PACIFIC Trial in Stage 3 Non-Small Cell Lung Cancer

Dr David Spigel provides information on the PACIFIC trial, including the 4-year update. 

Data from the PACIFIC Trial in Stage 3 Non-Small Cell Lung Cancer | Investigator Perspectives

EP 1: Understanding the PACIFIC Trial

EP 2: The Role of Molecular Testing in Lung Cancer

EP 3: Toxicities Seen in the Treatment of Lung Cancer

EP 4: Special Patient Circumstances and Immunotherapy

EP 5: Immunotherapy in Non–Small Cell Lung Cancer