Established Management Paradigms and Biologic Rationale for the Evaluation of Immune Checkpoint Inhibitors for Patients with Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

DR JOLLY: Okay, so I’m going to start — I know a lot of you are familiar with lung cancer treatment in general, but I’ll start with a little bit of background, some radiation advancements, talk about immunotherapy, and the PACIFIC trial we’ll just touch upon because we’ll be going through that in more detail.

About a third of non-small cell lung cancer patients are diagnosed at Stage III, so locally advanced. Standard of care for inoperable patients is concurrent platinum-based chemotherapy with concurrent radiation to 60 Gy and now with durvalumab on the back end. Survival with chemoradiotherapy alone has been pretty poor. Older data has shown median progression-free survivals of as low as 8 to 10 months. Five-year overall survival is 15% to 25%. And we know that this is a very aggressive disease. We also know that normal lung is radiosensitive, so we’re balancing pneumonitis and esophagitis and other toxicity as well. And other things that we’re now learning more and more about is cardiac function, patients who have poor pulmonary function, how to better treat them with radiation treatments.

Kind of going way back, RTOG 7301 set the standard for radiation alone at that time, and real poor 5-year overall survival, but the dose, even back then, was 60 Gy in 6 weeks. Subsequently, chemotherapy was added in a sequential manner and unsurprisingly did show a benefit of adding chemotherapy to radiation.

And then the next step was the sequencing, and after many studies, and then eventually there was a meta-analysis as well, concurrent chemoradiotherapy became the standard, really, for just about 2 decades, showing with the concurrent chemo having at least 5% 5-year overall survival benefit. And then the question that came up was whether we should be increasing radiation dose from 60 Gy, and the RTOG-617 randomized patients to 60 versus 74 Gy. There was also a question of cetuximab in this study, whether the addition of cetuximab would make a difference for these patients.

And the results of this study were rather surprising, especially in the era where SBRT had become more and more common, was showing very good local control. I think it was anticipated that the higher dose would result in improvement, but unfortunately it did not, and the 60 Gy arm remained the standard.

There are many factors that have been analyzed since the results of the study have come out with regards to PTV size, heart volume. Cardiac toxicity is becoming looked at in more detail. And subsequent studies since this have shown that cardiac toxicity may have been an attributing factor, so the heart V5 and V30. And now current studies have limited dose to the heart. Can’t say if that explains everything here. But nonetheless, the 60 Gy, 6 weeks, standard — and furthermore, there was no advantage of adding cetuximab for these patients.

And as I’m sure most of you know, radiation planning has a big factor to play, as well as our technology is improving our ability to follow the tumor, do 40 CTs, SDX, follow the tumor and decrease margin sizes. That does allow us to potentially give higher doses. And the dose constraints and compliance criteria are obviously very important. In the RTOG-617, the heart criteria was a Priority 3 and was not monitored as carefully. And obviously the emphasis, especially when you’re trying to give a higher dose, was on lung V20 and mean lung dose.

After that, with all the successes we’ve had in immunotherapy in melanoma and in metastatic lung cancer, a lot of emphasis was placed on trying to integrate radiation with immunotherapy. The integration of radiation with immunotherapy is being looked at preclinical setting, as well as now in the clinical setting. Increasing the antigen release with the immunotherapy, the tumor neoantigens that are formed, then you have the PD-1, PD-L1 upregulation, and the immunomodulatory cell surface molecules are upregulated, and with all the cytokines that are released, it increases the immune response.

The radiation itself can play a factor. This is mostly right now in the preclinical setting that we’ve seen that if you have radiation, the tumor antigen release is increased, and you can get upregulation of the entire response. And anecdotally, a lot has been looked at with the abscopal effect, and we’ve talked about this: Is this just a unicorn, or is this something that we’re actually going to see in some way?

And for those of you who may not be familiar, the abscopal effect is the idea where you treat 1 tumor to a high dose, and in the first picture, the pretreatment, there’s multiple other areas, and with both SBRT and radiation, you can see in the post-treatment, other areas have shown a response because of the immunogenicity effect of the radiation. This is obviously very exciting, and it’s something that there is a lot of preclinical data now looking at. But is it ready for prime time? I think the answer’s probably no. But a lot of clinical trials that we’ll talk about evaluating this.

This set the stage for the PACIFIC trial, which is for the same population and who undergo chemoradiation as previously described and then are randomized to 1 year of durvalumab versus placebo in a 2:1 randomization with the endpoints of progression-free survival and overall survival. And the results of this study Dr Langer will go through in a lot more detail, but a couple of things I wanted to highlight is (1) that patients who have a PD-L1 less than 1% did not show improved survival.

But with that, this was an ad hoc post hoc analysis, and the number of patients was small. But otherwise, in the overall analysis, the benefit with the durvalumab was seen independent of the PD-L status, and as Dr Langer was alluding to earlier, that is why this is approved in the United States. It’s approved for all patients with Stage III lung cancer, independent of PD-L status. I believe in parts of Europe it’s less than 1% are not approved.

And the timing of radiation also does seem to maybe play a factor. Especially, again, going back to the immunogenicity effect of radiation, can see that patients who started durva sooner — so the way the protocol was written, it was within 6 weeks you had to start the durva. But patients who started sooner — and of course you can say that these were better performance status patients — had tolerated chemoradiation perhaps better, that they were able to start durva better, did show a better overall survival. And so does that mean that everybody who finishes chemoRT should start durva within 2 weeks of completion? Probably not. I mean, you have to look at toxicity and see how these patients are doing.

But it does make us think that usually we wait 3 months after completion of chemoRT, or at some institutions they might do a scan at 1 month. But the period of when this evaluation needs to happen is much sooner. And ideally starting these patients sooner is what we would like to do. The postchemo imaging as well needs to be done in a much quicker manner, whether it’s within 2 weeks of completion of radiation or no later than 4 weeks.

In summary, we now have a new standard of care. Stage III locally advanced unresectable non-small cell lung cancer should undergo concurrent chemoradiation to 60 Gy, followed by 1 year of durvalumab, and overall it’s well tolerated. Even though we will talk about the toxicities in detail of immunotherapy, should be started sooner. Again, this is somewhat practice changing that you need to consider that this needs to be done earlier.

Patients with PD-L1 less than 1%, and also the EGFR-positive patients, again, it’s a much, much smaller number of patients, post hoc analysis, but perhaps the benefit in these patients is not as great as the other patient population. And understanding radiation techniques now in the setting of immunotherapy does become more important. Things like the low dose of the lung, where we’ve allowed V5 to get very high, are those things that we now need to consider that previously we weren’t, especially as rotational IMRT goes up in the community? I think these are important areas of research that need to be evaluated going forward.

Integration of Immune Checkpoint Inhibition into the Management of Locally Advanced NSCLC

DR LANGER: First PACIFIC and then a straight Phase II using another PD-1 inhibitor, pembro, from the Hoosier Oncology Group.

Dr Jolly’s gone over this in great detail. I’ll gloss through it. But again, checkpoint inhibitors, as you’re all well aware, have demonstrated activity in advanced disease with a clear-cut survival advantage compared to docetaxel in second line and now is single agent in combination with chemo in first line versus chemo alone in a fit patient, doesn’t have a contraindication. It is now essentially standard of care in metastatic or recurrent non-small cell.

We know that enhanced efficacy in particular has been observed in minimal-disease states. Therefore, it’s particularly well suited as consolidation after definitive chemoradiation, where hopefully we have debulked the tumor with both RT and chemo. As Dr Jolly’s pointed out, we can upregulate PD-L1 and cause release of tumor antigen and proinflammatory cytokines, potentially enhancing immune response and as well recruit T cells to the tumor bed. And there are multiple preclinical murine models that have shown that PD-1 therapy can enhance the efficacy of radiation via T-cell-dependent cytotoxic mechanism. This has been seen in GBMs, in breast, colorectal, melanoma and lung xenografts.

Here’s the PACIFIC trial. Dr Jolly showed you the outline. Again, this is a unique trial. It was a 2:1 randomization of durva versus an IV placebo. It was given every 2 weeks. Patients had to successfully complete chemoradiation and have no evidence of progression. Hence this paradigm shift to getting scans very quickly after the chemoradiation was completed. They needed a minimum of 2 cycles of chemo, at least 2 full-dose platinum equivalents and had to have good performance status. And the coprimary endpoints were PFS and OS.

The original publication just 2 years ago in the New England Journal showed a major, unprecedented improvement in progression-free survival, essentially a tripling in PFS. Again, the shot clock starts after the chemoradiation. Unlike our previous studies, where the shot clock started at the beginning of chemoradiation, you can see probably another 2 months to adjust this for our standard paradigm. But nevertheless, 5.6 versus 16.8 months. A 17% advantage at 18 months, so those of you who voted between 15 and 20 probably had the right answer. That’s the absolute advantage. The relative advantage is a lot higher. It’s actually in that 60% or 65% category.

If we look at PFS by subgroups, pretty much a benefit across the board, particularly for younger patients, those under 65, with a hazard ratio of 0.43. And in the initial analysis, regardless of PD-L1 status, but notice they use 25% as the cut point, not 1% or higher, or zero. And I’ll show you those data a little bit later. Relatively greater PFS benefit for those with higher PD-L1, not terribly surprising. Hazard ratio of 0.41. And the data are minimal for the EGFR-mutant group. This is 43 patients out of well over 700 accrued. You do the math, that’s just about 5%. And at least the hazard ratio is favoring durva. Very wide confidence intervals because there’s such incredibly small numbers. And we don’t have data for ALK or really for any of the other oncogenic drivers.

Three-year update this year at ASCO, and we actually see a survival advantage that was reported last year at World Lung and shown again this year by Jhanelle Gray, with the same morphology to the curves. At 3 years we see 57% alive, durva arm, placebo group 43.5%. Again, the placebo group doing as well or better than historic controls, which I think is quite important. An aggregate of 31% reduction in the risk of death with a hazard ratio of 0.69.

Ahh! Here’s the PD-L1 analysis. Dr Jolly alluded to this. It’s in the New England Journal paper, but you have to be really determined to find it, because it’s not in the actual paper. You have to click the supplements online. Hidden truths that are buried in the New England Journal. But if we look at OS, less than 1%, at least in this subgroup. No obvious advantage, even though there is a trend toward advantage for PFS.

But as Dr Jolly’s pointed out, you’ve got to be really careful. This is a post hoc analysis. Fewer than 60% of those enrolled on the study had adequate tissue for PD-L1 assessment. Small numbers were actually PD-L1 zero. About 20% of those accrued at most. At 3-year follow-up, when Dr Gray updated the analysis at ASCO, that hazard ratio dropped from 1.36 to 1.14. At most I would argue this is hypothesis generating. It does give us some cause for concern. And certainly EU has taken this to heart. In Europe the approval is strictly 1% or higher. In the US it’s regardless of PD-L1 status.

I had a lot of concerns when the study first came out, some of which have been addressed, some of which have not. The original presentation, of course, was blinded to OS, and yet it did result in an approval. That’s since been addressed, first by the press release and then by the New England Journal paper and the update this year at ASCO. And certainly the survival benefit is holding up, and that too has been unprecedented. But the data on PD-L1 less than 1% still give us pause.

The control group, as best I can determine, really underperformed with respect to PFS. This is still unexplained. We’d expect a 10- to 12-month median PFS in this population. Even if we deduct for the 6 weeks of chemoradiation, that drops to 8.5 months or 7.5 months, not 5.6 months. We have no idea of the percentage that underwent PET imaging prior to enrollment. The study enrollment occurred after chemoradiation. Case report forms did not account for pretreatment PETs, which are pretty routine, at least in North America, but not necessarily in the rest of the world. Needless to say, 15%, 20%, 25% of our patients might have had occult metastatic disease that was otherwise undetectable. And naturally, durva’s going to do better than placebo in that group.

There was some imbalance in the percentage of patients with greater than 25% PD-L1 expression that actually favored durva. This is, I consider, a lucky break, although it wasn’t a major imbalance. And no data on the percentage who received less than 60 Gy or the nature of subsequent or concurrent chemo. The latter is addressed by supplemental tables in the original New England Journal paper, and it’s a pretty good distribution between cisplatin-based regimens and pac/carbo. We still need the information on the former and on follow-up treatment, as well as the patterns of recurrence.

The Hoosier Oncology Group has mounted a straight Phase II of pembro in the same setting, locally advanced disease. You can see the fairly standard chemo regimens that are used here. Better defined radiation dose, 59 to 66.6 Gy. Those with stable disease or response going up onto pembrolizumab every 3 weeks as opposed to every 2 weeks for up to a full year.

Of note, a majority were unable to complete treatment. Only 43.5% were able to get through a full year. Disease progression, AEs were the leading cause. And if you look at the PACIFIC trial, it’s a very similar percentage. About 42% were able to get the full year of treatment. The median duration of treatment was roughly 9 months.

If we look at the data, it certainly looks comparable to PACIFIC. Again, these are cross-trial comparisons, but very similar trials. I think it helps at least inform the discussion. PFS and overall survival numbers are virtually identical. And if we look at time to metastatic disease or death, which is a surrogate for survival, maybe about 7 months better. But again, these are just a simple Phase II. And this is a new concept that hadn’t previously really been reported typically in older trials, this TTMDD that seems to have evolved as a new endpoint.

Our institution, in concert with Robert Wood Johnson, led there by Salma Jabbour, looking at both concurrent and consolidative pembrolizumab, 3-by-3 design starting at least initially after the chemoradiation’s done and then halfway through chemoradiation and finally day zero with dose escalation. Primary objective here was safety. Treatment was continued, as with all of these studies, for about a year. And again, that’s an empiric concept. We have no idea of the ideal duration of treatment.

And the DLT was defined as Grade 4 pneumonitis within 1 cycle of pembro. Twenty-three subjects enrolled through November. This was presented as a poster at ASCO. Fairly standard demographics, although the majority were female, vast majority were Stage IIIB, and there were no DLTs, at least as defined on the study upon the full-dose regimen. Eighteen percent Grade 3 or higher immune-related AEs. If you look at the overall numbers, though, about a quarter of patients had at least Grade 2 pneumonitis. This is still not a trivial issue, and Dr Patel will go over that in a bit more detail. PFS here was about 20 months for those who received 2 or more cycles of pembro.

In conclusion, based on the positive PFS and overall survival results, durva consolidation for up to a year is now the standard of care in locally advanced non-small cell patients who’ve completed chemoradiation who are truly eligible for immunotherapy. Pembro consolidation performs about on par with durva, though with slightly higher pulmonary toxicity. About 6% Grade 3 and higher compared to maybe 4.5% for durva. In both cases the survival data seemed to exceed historic controls.

There are a number of open questions. Do all PD-1 and PD-L1 inhibitors have similar efficacy and toxicity? What is the optimal duration? Should it be a year? Should it be less? A majority did not get the full year of treatment. What about the role of concurrent as well as consolidative? And Dr Loo will explore some of that at the end. What about IO/IO combinations? And finally the role, if any, of biomarkers. Critically, should we consider alternative strategies in those with no PD-L1 expression, as we’ve discussed?

Incidence, Recognition and Management of Immune-Mediated and Other Toxicities with the Use of Anti-PD-L1 Antibody Therapy for Locally Advanced Disease

DR PATEL: We’re going to just talk about the rate of high-grade adverse events, look a little bit closer at treatment discontinuation and Corey mentioned that as well as really end with a primer on how do you assess toxicity and what do you do about it?

Overall I think we can all agree that durvalumab was very well tolerated in the PACIFIC trial. If you look at any events, they were well distributed. Ones of, I think, interest are pneumonitis or radiation pneumonitis. When we look at all grades in the durvalumab arm, it was 33.9%. But when we really honed down on what’s clinically significant to us, Grade 3 and 4, the rate was only 3.4% as opposed to 2.6% in the placebo. And I think this was really something that many of us were surprised about when it was first reported. We expected there would be higher rates of pulmonary toxicity, but certainly this was very reassuring and I think much better than many of us expected.

Again, looking at Grade 3 and 4 toxicities, a little bit higher, a smidge higher with durvalumab, 30% versus 26%. But this is tough therapy, right? Patients are getting radiation. Patients are getting chemotherapy. And historically we would think that it would generally take some time for patients to recover completely from therapy, from things like esophagitis, from pneumonitis, from fatigue. And so this is a tough population. And so it’s not unexpected to see some of these toxicities.

But what’s most important, I think, is the toxicities that led to discontinuation, only about 15% in the durvalumab arm. And again, as we talked about with the rates of pneumonitis, much lower than one would expect and, I think, of high-grade pneumonitis in these patients.

Is there a way that we can predict which patients will really have pneumonitis or when that pneumonitis will really transpire? And unfortunately I don’t think we do have a great handle on this. We know that the time of onset to pneumonitis was similar between both arms, really, in the durva and the placebo arms. The duration was about 2 months in both arms, so really nothing there to help us.

Overall, the treatment exposure was pretty similar as well. The placebo arm’s on the orange, the durva in the blue, and you can see that there’s very little difference in both of these rightabout 16 weeks.

It’s also interesting to think about this is a population in which we don’t have a lot of data regarding the radiation, as it’s been talked about. We don’t really have a great handle on whether there’s toxicity associated with prior RT dose. Again, there was a broad range in radiation delivery, and we await those details.

Interestingly, so remember, in the PACIFIC trial patients could not get consolidation chemotherapy. Patients got only concurrent therapy, and some patients got induction. Something we see often in the rest of the world, often patients will get started with a cycle or two. Looking at this data, it seems that early induction was associated with less pneumonitis. It’s a little bit counterintuitive in the United States. We tend to use induction therapy for patients who have very bulky tumors, but probably it was a smaller field for everyone, and so that was the standard of care in the rest of the world. Perhaps that explains a little bit less pneumonitis in these patients.

Some interesting factors, looking at potential factors, smokers and nonsmokers. The odds ratio was 0.67. I think really to pull out of here histology. Patients with nonsquamous tumors had a higher rate of pneumonitis. Patients with worse performance status had a higher rate of pneumonitis, again, PS1. And then region. This is really impressive — a hazard ratio 5.4, so a much higher risk of developing pneumonitis if you were from Asia. I think those are the outliers.

Prior COPD we talk about, and it’s 0.73. Certainly a little bit of a change there, but these patients may have been underdiagnosed. I don’t think we have pulmonary records of their pretreatment PFTs, for example.

These are the 3 factors. Certainly, Asian population was much higher, and we see that across all chemoradiation trials. Histology, higher again in adenocarcinoma, and it may also be higher incidence in Asia. And as one would expect, a less robust patient might have a higher risk as well.

In conclusion, this is safety conclusions from PACIFIC. Pneumonitis occurred, but high-grade, 3 and 4 events, were in similar rates whether you received active drug or placebo. Most patients had Grade 1 or 2 events. The time of onset, this really, you can’t tell the difference and goes as one would expect, perhaps radiation pneumonitis. There’s really no difference. Patients who were treated in Asia, patients with nonsquamous histology and perhaps who are less robust have a higher incidence.

Another trial that you may have heard of is the European trial led by Solange Peters, the ETOP NICOLAS study. And in this study, patients received nivolumab during chemoradiation. When nivolumab was given during chemoradiation, this group of patients had an 8% risk of Grade 3 pneumonitis — Grade 3 or above pneumonitis, so 10%, so certainly higher. And this bottom graph again shows how it’s a little bit difficult to assess when it’s going to happen. It can happen almost at any time. There’s really no clear factor of patients who had worse-grade pneumonitis, whether it was early onset or late.

We look across multiple trials with chemoradiation. The PACIFIC trial, Greg Durm’s trial from Hoosier Oncology Group, DETERRED and NICOLAS. One thing that I think stands out is the PFS across these trials is pretty similar, about 17 to 20 months. If you look at the pneumonitis rates, and sorry this line’s a little bit off, but the first line is any grade of pneumonitis. That’s this line across here. It’s a little bit higher in the PACIFIC trial, pretty consistent in the DETERRED trial, but somewhere between 17% and 30%. Again, reassuringly in these trials, Grade 3 pneumonitis was quite low. I think the outlier is the concurrent nivolumab in NICOLAS at 10%. Rates of discontinuation are fairly similar, between 10% and 20%, a little bit higher on the DETERRED study.

Now, one of the things that’s so difficult to discern is whether toxicity is from prior therapy, from chemoradiation or durvalumab. We know after treating hundreds of thousands of patients with immunotherapy that almost any symptom could be immune related. And I think what’s difficult is that there is a lack of clear, timely relation to treatment, and you can have a very late occurrence of therapy. So, for example, last week in clinic I saw a patient who’d received ipi/nivolumab 6 months ago and then came in with disabling arthralgias, had been off of all immune therapy for 6 months.

Diagnosis can certainly be a challenge. We have some idea about what kinetics for most people look like. This was presented at ASCO several years ago. We know skin toxicity is the most common. That tends to be between 3 and 6 months. Gastrointestinal toxicity, the kinetics tend to be a little bit tighter, pretty early-onset toxicity. But then if you look at endocrine effects, wow, so almost 8 months after your last dose of pembrolizumab, for example, you could end up with profound hypothyroidism. These are things that you just need to factor when you’re looking at all patients. Pulmonary toxicity tends to be a little bit earlier on, between 3 and 6 months as well.

The other issue is that in particular for us, who treat the chest, the spectrum of radiographic manifestations of immunotherapy can be broad. It can look like pulmonary edema. There can be nodular infiltrates. There can be widespread areas of crazy paving to suggest an organizing pneumonia. Patients can develop a diffuse interstitial pattern that looks like edema. And so it’s very difficult to make the call based on radiographs alone. Moreover, the predominance of the changes might be in the radiation field. And so it’s difficult to tell what’s really the active agent there, whether it’s early radiation pneumonitis, late radiation pneumonitis or immunotherapy toxicity.

For that reason, we’ve spent, I think, a lot of time as a medical community trying to understand how to grade these patients and how to adequately treat them. ASCO, NCCN, EMA, multiple organizations, CTSI, have societal guidelines on how to manage these patients. Julie Brahmer was the head of the steering group, and if we look at pneumonitis, which we just call diffuse inflammation of the lung, we know that these patients need to be followed closely. They need chest x-rays. Now, our vital sign in clinic is always an ambulatory pulse ox, because we can pick up small decreases that we may be able to nip in the bud.

Grade 1 or patients who tend to be asymptomatic, it may be in less than 25% in the lung parenchyma. We see it when we’re getting their CT scan. Generally for these patients, we hold the immunotherapy. I usually get another CT scan in about 4 weeks to assess. It may be a cycle or two that we’re holding. One piece of it is very close follow-up. This has made all of our clinics balloon in the past couple of years, but these patients need to be evaluated weekly until we know that they are stable or improving.

Patients with Grade 2 toxicity have symptoms. They’re the ones that come in and say that they are a little bit more short of breath — up to 50% of their lung parenchyma’s involved. Again, here we hold the immune checkpoint inhibitor until there’s resolution to at least Grade 1 or less. For these patients, we start steroids, and I usually start a prednisone dose of about 1 mg/kg for Grade 2. Sometimes we’ll go up a little bit higher. Often we’ll get them into pulmonary the same day. We’ll try to have our interventional pulmonologist meet them and consider bronchoscopy if there’s any question that it could be something else, a superimposed infection.

Again, these are patients that we’re monitoring frequently. Almost all of our patients now go to Amazon and get a pulse ox delivered and MyChart us with details, which I think is important — that shared decision-making.

Grade 3 and Grade 4 is severe toxicity. These are patients who are generally hospitalized. If patients have Grade 3 and 4 toxicity, almost always I permanently discontinue therapy. We start higher-dose steroids, IV steroids, and often work with our multidisciplinary team. In our hospital we have a rheumatologist and a toxicity board that works with us. We have a pulmonologist, a nephrologist who is interested in managing these toxicities.

What’s key is that the management really depends on grade. And so it’s important as we educate those thatwork with it. There are guidelines. Like it says, how many times are you having diarrhea? What percentage of your skin is covered with rash? If you use these guidelines, that will help with management significantly. There’re interactive websites. Know that by and large, steroids are the mainstay of therapy. For fragile diabetics, for people with other comorbidities, that can be tough, and we use other immunosuppressants.

Generally I would say completely hold immunotherapy or have frank conversations about discontinuing immunotherapy if patients end up with Grade 3 or 4 toxicity. Certainly we’ll see Grade 3 toxicity in things like hepatitis, for example. Often that will resolve very quickly, and we can restart it. But Grade 3 pneumonitis is a big deal, right? Patients are hospitalized on liters of oxygen. And then again, consideration of re-treatment with immunotherapy, but generally our understanding of the kinetics is that these drugs are in our patients for some time, and so it makes sense to hold until toxicities are resolved.

Little other things to think about. We start steroids, but remember, the patient should probably get GI prophylaxis, to think about PCP prophylaxis. Remember that patients who are on steroids need frequent evaluation. And again, that’s changing how we run our clinics a little bit, and our workflows, but there are ways to do it as a team-based sport. And this is really an important part of it, is that it’s truly multidisciplinary.

Ongoing and Planned Clinical Trials of Immune Checkpoint Inhibitors for Patients with Nonmetastatic NSCLC

DR LOO: Just briefly, I was charged with talking a little bit about ongoing and planned clinical trials of immune checkpoint inhibitors for locally advanced non-small cell lung cancer, and in 8 minutes, the high-level summary is, there’s a lot of trials.

I obviously won’t be able to go over them individually. I’m just going to highlight a little bit. This has already been discussed tonight. I just wanted to highlight here, not go back through the trials, but just to highlight some numbers to kind of create a mental benchmark. In the United States, we consider RTOG-0617 to be the benchmark results, a study that had high-quality radiation therapy, good quality controls on both chemo and radiation. And so the benchmark outcome in Stage III lung cancer would be 29 months’ median survival and 32% 5-year survival. And then you can see the progression-free survival, of course, is shorter than that. It was about a year median progression-free survival.

The standard of care, of course, changed with PACIFIC. And some of the questions we already discussed earlier: What about the issues of the quality of control of the radiation, which wasn’t part of the study? And to what extent is potentially the immunotherapy overcoming radiation therapy is not totally standardized? But if we look numbers to numbers and compare to RTOG-017, on the placebo arm of PACIFIC we see that the overall survival results are actually quite comparable, almost the same as what we saw on the good arm of RTOG-0617. Now, Dr Langer pointed out earlier that the PFS numbers don’t seem to be quite as good, so there’s a little discordance there. But the durvalumab arm was certainly better, just comparing numerically.

Now, you also pointed out the difference in time. When do you start the clock? And so in principle we might say that we should add 2 months to the numbers on the PACIFIC trial, because it started after the chemoradiation. On the other hand, there was a selection factor, right? Basically anyone who had explosive metastatic disease wouldn’t be able to make it on. You’re excluding some of the worst patients. I think it may go a little bit both ways.

But one thing that I did want to point out is, the RTOG-0617 United States standard — we may or may not have milked kind of the optimal chemoradiation out of it, so this is not to compare to that, but these are prospective data on the left-hand side from a randomized Phase II trial of about 100 patients. The study question was with or without cetuximab, which didn’t make a difference. But if you look at the outcomes of the chemoradiation, this is using a regimen that was accelerated and a little bit dose intensified, so 66 Gy in 24 fractions, so under 5 weeks, accelerated radiation therapy. And the chemo was a little different. It was low-dose daily cisplatin as opposed to the full-dose chemo that we tend to use.

But the outcomes on this are quite remarkable in kind of a balanced mix of Stage IIIA and IIIB. The median survival is about 3 years, so much better than what we saw on 0617. And the 5-year survival is 40%. And then on the right is the same regimen, but this was in a separate single-institutional retrospective study but a larger number of patients, essentially mirroring the exact same results.

The point being that maybe we can do better with just chemo and radiation than we have in the past. That remains to be determined and optimized further. But if you look at some of these numbers, we’re getting to similar numbers to the good arm of PACIFIC, right? And so if we had optimal radiation combined with immunotherapy, would the benefit be better or less, right? And it could be either way. It could be that the best combination is the best radiation and the immunotherapy, okay?

Moving on to some ongoing trials, there’s a few now that have actually some early outcomes data, and you heard Dr Langer present earlier about the adjuvant pembrolizumab trial. This one is one that looked at 2 strategies. One was to add adjuvant atezolizumab after chemoradiation and then after a run-in for safety. Then it moved on to doing concurrent atezo with chemoradiation, followed by the adjuvant. And, interestingly, in this one there’s also adjuvant chemo, so this is a carbo/paclitaxel regimen.

And that was one of the questions about PACIFIC is, what do you do with the extra cycles of carbo/paclitaxel that you might or might not give after the concurrent? And this one has both.

And so a very small study and some early results. Numbers to numbers it doesn’t necessarily look like a big improvement over PACIFIC, but the interesting thing is that there seemed to be a little bit better outcome on the concurrent plus adjuvant versus the adjuvant alone with atezolizumab, okay? And that’s just comparing to the PACIFIC numbers.

These are slides that were presented by Francoise Mornex at WCLC last year, and I’m not going to go through all of that, but she did a very nice compilation of trials at the time combining immuno and chemo and radiation for locally advanced lung cancer. These are a bunch of trials that are looking at that similar PACIFIC-like consolidation approach.

And you heard the one that Dr Langer described earlier, and then the DETERRED trial is here. This one is actually both. It was both the adjuvant and concurrent plus consolidation. And then these are a bunch of trials that are looking at the concurrent and consolidation approach, and I’ll just mention one of them here, which is, this is the PACIFIC-2 trial that is opening through NRG, and what this is looking at is, essentially the PACIFIC trial is the control arm. And then that’s compared against the chemoradiation plus concurrent durvalumab followed by durvalumab. And then there’s additional approaches, including bringing the immunotherapy up front before the chemoradiation as induction.

There’s looking at checkpoint inhibitor combinations, the ipi/nivo versus nivo alone, and so on. And then there’s a couple looking at radiation-specific techniques, including a stereotactic boost or proton versus photon.

But I wanted to talk about one in particular, which is the NRG-LU004. This is an interesting one. It takes patients with high PD-L1, and what it’s studying is the replacement of chemotherapy with immunotherapy. It’s concurrent durva with radiation, followed by consolidation durva.

And there is a randomization to look at 2 different radiation regimens. The radiation regimens are 60 Gy in 15 fractions for 3 weeks versus in 6 weeks. And the 60 in 15 is an approach that’s been evaluated in essentially poor performance status patients who can’t take concurrent chemoradiation, but now it’s being brought up to the Stage III population but with the addition of the immunotherapy.

And then I just wanted to close with a couple of comments about going beyond locally advanced. This study was actually mentioned, published by Dr Formenti, and this was looking at, in metastatic disease, giving — this is a CTLA-4 inhibition plus radiation therapy to a single lesion out of many and looking at that abscopal response. And it produced a higher than expected abscopal response rate outside of the treated field. But I think one of the important points of this one is looking at the biomarkers that those patients who had a response had immunologic markers that changed quite a bit. A rise in interferon beta as well as both expanded and contracted T-cell clones.

I think that highlights the issue that it’s going to be more than just PD-L1 status and so on, or tumor mutational burden. There are dynamic biomarkers that we could and probably should be looking at going into the future.

And then just a couple more interesting trials that were recently published. This is the pembro/RT trial. This was a randomized trial that looked at patients with metastatic disease, on pembrolizumab, and they got plus or minus radiation therapy to just a single metastasis. And numerically the PFS and overall survival were both increased in the patients who had radiation to just 1 lesion. And it wasn’t totally ablative radiation. It was 8 Gy times 3. But a pretty interesting result. Now, this did not meet their prespecified significance criterion for a statistically significant benefit but numerically showing a pretty interesting trend.

And then sort of a complementary trial from UPENN, and Dr Langer I hope will forgive me for calling this the “PENNbro” trial — but this was a different approach where — and it was a single-arm study — where the pembrolizumab was combined with radical local treatment of all metastases in the oligometastatic setting. And so the comparison is against historical controls of oligometastatic disease but showing a pretty promising signal with a median overall survival of over 40 months. And this is in metastatic disease, and a median PFS of 19 months. Looking better than actually our Stage III studies in metastatic disease.

An interesting analysis that came out of both studies is, what about the PD-L1 status? And it kind of went in different directions. The pembro/RT trial — it was actually those patients who were PD-L1-negative that seemed to have the greatest benefit. And, actually, it reached statistical significance in that group. Maybe the irradiation of a single lesion was converting a cold tumor into a hot tumor. People who wouldn’t normally respond to the pembro appeared to get a benefit, whereas in this one it’s the converse. Now all the lesions are being irradiated, and those that seemed to do better had a higher PD-L1 status in the tumor. Maybe those patients who would normally be expected to respond better to the pembro are the ones who got a benefit. Interesting, very early data, but I think quite promising and shows the future direction.

In conclusion, immune checkpoint inhibition has improved survival over our historical standard of chemoradiation, and not a very old historical standard. I mean, this is a very dynamic field. The optimal integration is still something that is actively being studied, so the sequence, what IO combinations to use and even potential replacement of conventional chemotherapy. And there’s a question of whether the best approach with radiation combination is comprehensive irradiation of all known sites of disease, even in metastatic disease, or not. And I think an important point going into the future will be looking at the biomarkers beyond the PD-L1. Thank you very much.