Introduction

Welcome to this continuing medical education (CME) program entitled, “Post-ECC 2015 Review and Analysis: Current Science of Immunotherapies and the Management of Patients With NSCLC.” This CME activity is supported by an independent educational grant from Bristol-Myers Squibb Company and is provided by AcademicCME. Hello, I am Mark Kris, MD, from Memorial Sloan Kettering Cancer Center, and I’m very happy today to be joined today by two true experts in this field, M. Catherine Pietanza, MD, from Memorial Sloan Kettering Cancer Center and Corey Langer, MD, from the Abramson Cancer Center at the University of Pennsylvania.

This is an amazing time in thoracic oncology, to have not just new treatments, but a whole new array of medications to add into radiation, surgery, chemotherapy, and the targeted therapies that we already have. It is a tremendous opportunity first and foremost for our patients and also for oncology. It also makes our job much better because we can offer more, but it also makes it much harder, because we now have to find a way to learn about these new therapies and integrate their use into all the effective treatments that we now have at our disposable. That is going to be a huge challenge for all of us in the field over the next few years. There are four drugs either approved or in late-phase clinical trials. There is nivolumab, but we are going to call it “nivo” today. There is pembrolizumab, and we are going to call it “pembro” today. There is atezolizumab, and we are going to call it “atezo” today. And there is durvalumab, which we will call “durva,” but we won't have an abstract today on that topic.

A couple of starting points we will get back to at the conclusion, and I am going to ask the other panelists to speak on these as well. By looking at the medical literature and these abstracts, it is almost unanimous that these drugs work; there is no question that they work. There is also very little question that when one has a response, it is substantial; it’s important to the patient clinically, and it lasts a long time. It is very different from any other treatments that we have. We also are at some agreement that we don’t have a way of choosing patients to most likely have the best response. Even the best—and we’ll be talking about what best means—biomarker can predict response about a third of the time, and that is really not good enough. And, truly, the negative biomarkers do not

mean zero; sadly, many of the treatments we currently offer patients are very close to zero. So, it is very difficult to differentiate how these drugs differ among patients, particularly our cytotoxic drugs.

I’m going to put it out there, too, that we don’t see obvious differences between these drugs, and the other speakers may comment on that. We see toxicity profiles that are just a fraction of what we are used to, even with our targeted therapy drugs, let alone our cytotoxic chemotherapies. As far as we can tell today, whatever benefit these drugs can bring, they appear to be additive to our other treatments; they aren’t replacing other treatments. I think it is that factor that makes us think these are a big step forward. Before we start going into some of the specific abstracts from the conference, Corey, Kathy, do you want to make a few comments?

Dr. Langer: I agree with you wholeheartedly. I would say that these drugs are not replacing our current compounds, but they are displacing them. For instance, the landmark result—which was extremely exciting—of the CheckMate 017, 057 trials that led to nivo’s approval in the second-line setting essentially relegated docetaxel—our formal standard of care in the second-line—to either third-line, or one might argue, clinical irrelevance, considering the toxicity profile. I agree as well that we do not have consistent, reliable, binary biomarkers the way we have for targeted agents, particularly, EGFR mutations or ALK translocations. Anecdotally, some of my best responses with the pembro compound were observed in patients who were programmed death-ligand 1 (PD-L1)–negative. When it comes to toxicity, it is important not to conflate the side effects of the programmed cell death-1 (PD-1) and PD-L1 inhibitors with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors. Not only is there a distinction with standard cytotoxics, but there is a major distinction with other immunotherapies. These drugs are far less toxic than ipilimumab and many of the other agents that are used in immunotherapy.

Dr. Kris: Cathy?

Dr. Pietanza: I just want to reiterate the same points. These drugs have been found to be effective. They were using them in place of docetaxel for second-line, and they can be

used probably beyond second-line with good efficacy. Some of these abstracts we’ll review today will show that.

Dr. Kris: What we’re talking about today is something that I think many audiences don’t usually think about, and that is that abstracts presented at the European Cancer Congress (ECC) and the European Society for Medical Oncology (ESMO). I think it speaks to the global nature of our fight against all cancers and drug development that breakthroughs can be reported now at just about any conference and anywhere in the world. I think that’s probably a good thing—the word gets out faster and spreads.

POPLAR Trial

Let’s get to the first abstract that we want to talk about. Corey, do you want to talk about that?

Dr. Langer: Sure, I’m privileged to talk about the POPLAR trial. Earlier data were presented on this trial at the American Society of Clinical Oncology (ASCO) meeting and then updated at the World Conference on Lung Cancer (World Lung) in Colorado. This was a randomized trial of the PD-L1 inhibitor, atezolizumab—which is a bit different from nivo and pembro—vs the standard of docetaxel in the typical setting of second- and third-line. This was a fairly large trial with nearly 300 patients randomly assigned in a 1:1 fashion to either docetaxel or to atezolizumab. Patients were also assayed for PD-L1 expression, which was collected prospectively and then centrally evaluated. They used an interesting scale that was essentially immunohistochemistry (IHC)-based with scores of 0, 1, 2, and 3. Zero is pretty obvious, 3 is pretty obvious, and 1 and 2 can be a bit nebulous. The primary endpoint of this trial was overall survival (OS), and 287 patients were randomly assigned. There was a fairly typical histologic breakdown, with two-thirds being nonsquamous and about one-third with squamous histology. Across the board, one sees an improvement in survival in the intent-to-treat population, with a fairly impressive hazard ratio of 0.73 and the P-value of .04, which I think is an improvement from the ASCO presentation and is quite noteworthy. Of tremendous importance, those with high levels of IHC expression, both at the tumor level as well as in the immune stroma (the microenvironment surrounding the tumor), had a survival benefit that was even more pronounced. They had a relatively better hazard ratio (0.49) and a P-value that was approaching significance. On the other hand, of those who had no IHC expression of PD-L1, there was very little difference, if any, between the control arm—docetaxel—

and the experimental agent, atezolizumab. It should be noted that atezolizumab is not yet FDA-approved in the US, at least as of November 2015. However, we anticipate some sort of approval in the next 4-12 months. So, I believe the conclusion is that it is salable that survival was better with atezolizumab monotherapy compared with docetaxel. In this regard, the results mirror those observed in the CheckMate trials for nivo vs docetaxel in squamous and nonsquamous populations. In addition, PD-L1 expression seemed to correlate fairly strongly with the relative degree of benefit. There were higher response rates, greater progression-free survival (PFS), and greater magnitude of survival difference observed in those whose tumors had the highest level of expression of PD-L1. As a follow-up for this trial, there is a much larger phase 3 trial called OAK that will hopefully confirm these results and lead to the approval of atezolizumab.1

Dr. Kris: Just to add something to your comments, I’m struck by the results in the patients who had no expression or the lowest expression. It showed a comparable survival and also comparable rates of response—8% vs 10%. One quandary we now have is the selection of these agents by these tests and also the lack of a better alternative. When one looks at this trial, there were 4 times as many grade 3 and 4 toxicities with docetaxel than with atezo with comparable survival and response rates. Even in the patients who were negative, one would want to give atezo.

Dr. Langer: Absolutely. I think even though we failed to show a survival benefit, it may be a detriment for some to balance in PFS in that group. Toxicities are an order of magnitude less with these new compounds compared with docetaxel.

Dr. Kris: And when one lays out the choices to that patients, there aren’t a lot of choices here. People say, “Let’s try this first and have the other as a back-up.”

Dr. Langer: You still have chemo as a back-up.

BIRCH Trial

Dr. Kris: Continuing on our tree theme here, we’re moving on to the BIRCH trial. Cathy, do you want to tell us about BIRCH?

Dr. Pietanza: BIRCH also used atezolizumab and looked at patients who needed to be treated in first-, second-, or third-line; the eligibility criteria did include PD-L1 selection. Here, they looked at a 2+ or 3+ cohort of patients; those were the patients who had the highest PD-L1 expression

and were eligible. They were treated every 3 weeks with the agent until progression of disease. The primary endpoint was overall response rate, and then they obviously looked at the survival rate. Interestingly, I think that the 650 patients who were treated and evaluated for efficacy and safety had the same demographics as our usual patients. This trial also included a cohort of patients who never smoked. BIRCH met its primary endpoint in all predefined subgroups—that means first-, second-, and third-line. Interestingly, the response rates were very similar, regardless of first-, second-, or third-line. Basically, these patients had prolonged PFS and OS, with a 6-month survival rate of approximately 80 months, whether they were treated in first-, second-, or third-line. This is unusual for our patients who are treated in second- or third-line. The toxicities seen were the ones occasionally seen with these agents—minor episodes of pneumonitis—and most patients had fatigue. Here, BIRCH showed that there was a response in patients treated in any line of therapy with prolonged PFS and OS. Again, these patients should have had some expression of PD-L1.2

Dr. Kris: So, I’m starting to call this the “blurred lines” trial. I think it speaks to a truth that when one has a biologically-based therapy, the lines absolutely don’t matter. The lines are, in many ways, a contrivance to get a quick drug approval in a patient population. It’s critical, because it gets it approved, and we can give it to our patients. But I don’t think this line of business defines how one should best use these drugs. That’s something I think only further research is going to straighten out.

Dr. Langer: I agree. I think that there is a tendency to pigeonhole various agents into lines of therapy, and we have patients who have been through many lines of therapy and may have had two or three different cytotoxics and exposure to tyrosine kinase inhibitors (TKIs). Remember, erlotinib is still approved in unselected patients in second- and third-line, so when one has exhausted possibilities, and particularly when one has observed a positive level of PD-L1 expression, the benefits seem to be independent of the line of therapy. I think that’s an important take-home message, particularly for the community.

Atezolizumab Combination

Dr. Kris: OK, let’s go back to Corey. This is another abstract on atezolizumab.

Dr. Langer: This is a combination of atezolizumab with standard platinum-based chemotherapy. It is a phase 1b

study, so fairly early on. Again, these combinations with atezolizumab are given at 3-week intervals, which dovetails quite nicely with our standard cytotoxic regimens that are also generally given at 3-week intervals. Responses were assessed primarily in PD-L1 expression, which was also centrally evaluated using the same IHC scale we’ve already looked at. This was a relatively small study with well under 100 patients. The chemo combinations were common to clinical practice: carboplatin plus paclitaxel, carboplatin plus pemetrexed, and perhaps for the squamous cell population, carboplatin and weekly nanoparticle albumin-bound nab-paclitaxel. In this highly selected population that would not have contraindications to the clinical trial, the response rates across the board were 50% or higher. But remember that we’re talking about 8, 15, 17 patients per treatment arm. Of particular note, whether or not it is going to carry through further in phase 2 or phase 3 testing, there were 4 complete responses (CRs) for the nab-paclitaxel plus atezolizumab combination. It is not uncommon to observe partial responses or remissions with chemotherapy alone and certainly with the newer targeted agents and now immunotherapies. But CRs are fairly rare in advanced non-small cell lung cancer (NSCLC). Granted, this is a small percentage, but it is certainly encouraging, particularly in a population that one might preferably use nab-paclitaxel—squamous cell or those over 70. But, it’s important to note that these are very early data. If one goes back to some of the early studies of chemotherapy—

Dr. Kris: Like the Langer trial?

Dr. Langer: Like the Langer trial in 1995. It’s been 20 years since we first published our experience with paclitaxel plus carboplatin. Response rates then were also in the range of 50%, even 60%. So, it will be several grains of salt until we’ve seen a much larger phase 2 or phase 3 effort. I think we have to interpret this with some caution.3

Dr. Kris: Yes, I think your point about the CRs is something we have to watch out for, and that would be a big development. And every 3 vs 2 trial, there’s more toxicity with the 3. I think the common toxicities one might see, particularly myelosuppression, seem to be a little more obvious, so be careful with that. I think that was even true with carboplatin and paclitaxel as well.

Pembrolizumab

Dr. Kris: I’m going to talk about the next abstract about pembrolizumab. Pembrolizumab was recently approved, though it was a different approval. It was associated with a

companion diagnostic, and the idea was that one would test for this companion diagnostic and use it to help select patients for this agent. The approval was in patients who had PD-L1 expression based on a specific companion diagnostic in the label. This trial looked at various dosages and schedules, and it’s frankly difficult to tell exactly what the best dose and schedule are. I think it is clear that there is benefit across all doses and the schedule of every two weeks and three weeks. I think what's very interesting here is the duration of response, and the most startlingly observation is the duration of response for all patients on this trial. For approximately 80 responders on this trial, the duration of response is 23.3 months. Speaking to one of the comments we made at the beginning, the responses here mean something to patients symptomatically, and they also appear to be durable—maybe even more so than our other agents. I think we’ve seen that pembrolizumab is an effective drug—the response and survival rates are in the same range as atezolizumab and nivolumab, which we’ll look into shortly. There are very encouraging data regarding duration of response, and we're happy to have another drug in this field. The more we have, the more opportunities we're going to have for better care for our patients. Cathy, Corey, do you want to add to this?4

Dr. Pietanza: I think that you brought up a very good point regarding the duration of response. In the patients who do respond, it is very notable and is much more than we see for our patients on chemotherapy.

Dr. Langer: It’s definitely longer than what we see with conventional cytotoxics. It is rare, particularly in the second- or third-line, to see a response to docetaxel or pemetrexed that goes beyond 6-12 months. Here, and in some cases, these response are ongoing at 1-2 years with relatively minimal toxicities. We don’t seem to observe the cumulative toxicity that we certainly see with docetaxel or even with pemetrexed. My patients have hyperlacrimation, peripheral edema, and sometimes late-onset of rash. We tend to think of some of these agents as relatively innocuous, but they’re not. I think the big confusion in my own mind is regarding what the optimal dose is. Is there an optimal dose? Does it matter? The other important distinction, as Mark pointed out, is that pembro is given every 3 weeks, as is atezolizumab. But the FDA-approved drug, at least for now, is given every 3 weeks.4

Dr. Pietanza: And both of these drugs will have, looking at the abstracts that Corey and I just presented, higher response rates for atezolizumab for having better responses. I think that’s what your abstract with

pembrolizumab points to. There are responses in patients who don’t have PD-L1 expression, and so that’s important as well.

Dr. Kris: And the challenge here is to keep our eye on this. Even with this selection, only a third of the patients had a major response. I think one thing that that I would say is that if one doesn’t have a response, then one doesn’t have the benefit from this agent. We're going to be challenged as oncologists to quickly identify the two-thirds of those patients who are not going to have response and to get them on something that will be likely to help them more.

Dr. Langer: I find this to be a major challenge, because we have observed this phenomena of pseudoprogression. When is pseudoprogression real progression? How much does one go beyond, say, 8 weeks of therapy before one switches to another agent?

Dr. Kris: One thing is that the randomized trials—and we’ll get to some of those—are a very rare phenomena. It is a well under 5% phenomena. Much more common is what we’ve come to term pseudo-pseudoprogression. And just like any other progression, it is considering progression if there is generally a symptomatic decline along with a radiographic change, and then it’s time to move on. That’s going to be our challenge—how to figure out how to do that.

Nivolumab

Dr. Pietanza: Moving on to nivolumab, the global issue that Mark discussed, and how globally these agents are similar. This was looking at nivolumab treated in squamous and nonsquamous patients in Japan and looked at the results of two phase 2 studies; 111 patients were evaluated. The responses were approximately 25%-30%, and the patients who responded obviously had the bigger benefits. The nonsquamous and squamous patients who responded had a durable response of approximately 80%. As I discussed previously, that is very notable. Median OS rates in these studies were not reached. Again, this is a global study reiterating the points that we see in the US and Europe.5

Dr. Langer: Yes, it’s comforting to know it is not a regional phenomenon, and it’s also nice to know that the responses and PFS are very similar around the world, which is not necessarily the case with some of the cytotoxics. For instance, for whatever reason irinotecan and platinum in Japan is the standard go-to combination for front-line treatment of small-cell lung cancer. But studies in the US and in Europe look no better than etoposide plus platinum.

So, I think it is important to understand that what we see in one area of the world can probably be extrapolated to other parts of the world.

Dr. Kris: I think a lot of those differences have to do with drug metabolism, there are clearly ethnic and racial differences there—probably less so than with the monoclonal antibodies. I think it's more biology-based.

Cathy, let’s continue with another nivolumab trial and some additional discussion on the nivolumab vs docetaxel trial.

Dr. Pietanza: This is looking at CheckMate 057 and the randomized phase 3 trial of nivolumab, docetaxel, and patient-reported outcomes. Patient-reported outcomes as a marker are becoming more and more important; the National Cancer Institute (NCI) has a trial looking at patient-reported outcomes. Here, patients self-reported their experience on nivolumab and docetaxel. So we know the trial found that patients had no overt toxicities, were able to stay on nivolumab, and had less decline of their symptoms. The adverse events were higher in the docetaxel arm as opposed to the nivolumab arm. As we know, the safety was favorable for nivolumab.6

Dr. Kris: Corey, do you want to make a comment?

Dr. Langer: I think this is an important, consistent theorem that has been seen across all the trials and is not restricted to nivolumab. We’ve seen a similar lack of toxicity with pembro and atezolizumab. We haven’t seen quite as many data with nivolumab, but I would be shocked if it were any different. But we're talking about a major order of magnitude of differences in grade 3 or higher toxicities of under 10% with the newer PD-1 and PD-L1 inhibitors, whereas with docetaxel, which is admittedly our most toxic cytotoxic, grade 3 adverse event rates easily exceed 50%. We don’t see febrile neutropenia, we don’t see neuropathy, we don’t see rash, and we don’t see the overwhelming fatigue that some of these folks develop. Even if the patient isn’t necessarily responding, at least they are not suffering with toxicity with these agents.

Dr. Kris: Echoing an earlier comment from Corey, I think anybody using these agents can see the kind of benefits that the patients have had regarding the CRs. I think it is important in this area that we move on. We want to move on. We want to cure patients. We want more on CRs. That's what we should be spending our research time on, and that is the trial that I want to see.

Ipilimumab and Nivolumab Combination

On to the next. I think seeing the developments in the melanoma field has made anybody studying patients in this space very anxious to try to combine checkpoint inhibitors—those targeting PD-L1 and those targeting the CTLA-4—and mirror the experience of patients with melanoma. The abstract shown here is an example of small study, about 50 or so patients, getting ipilimumab and nivolumab together. As one would expect, this is a nonrandomized trial. The feeling one gets from the data is that there is some enhanced benefit by combining the 2 in terms of effectiveness, and there also is enhanced toxicity. Its unlike, as Corey very accurately described, the kind of lack of toxicity that we see now with agents such as nivolumab or pembrolizumab. It is much more substantial, and when it happens, there is more profound toxicity, with the skin, liver, gastrointestinal tract, and lung leading the pack. This is an area worthy of further research, and we can learn a lot from our colleagues in melanoma. They have pioneered this research and have a lot of experience. Based on the melanoma literature, the biggest impact for the patients appears to be from nivolumab, and ipilimumab adds to that. Again, it's going to be our job as oncologists to determine who is going to be the right patient to add that substantial increased risk of toxicity for a smaller chance of benefit than nivolumab. That's going to be a tough decision-making process that we are all going to have to face going forward.7

Dr. Langer: I'm very concerned about that. The PD-1 and PD-L1 inhibitors are generally far less toxic than the CTLA-4 inhibitors. So the minute we start mixing and matching the two, we are raising the toxicity levels to those observed, with it being similar compounds. Our patients are quite a bit older and have far more comorbidities than the typical patients with melanoma, so the safety thresholds have to be reassessed. In the curative setting, I certainly would love to see these combinations explored further and even in certain refractory settings. For instance, there were data at ASCO and World Lung in small cell and the second- and third-line, particularly even chemorefractory, where this combination regardless of PD-L1 status resulted in selected prolonged responses. We typically don't see that with cytotoxics, so it needs to be set in specifics. A frail patient or a performance status (PS)-2 patient who we might treat with just with a PD-1 inhibitor alone, I would be a bit reticent of doing a combination.

Dr. Kris: We are a part of these trials and I have to say I thought long and hard about recommending this regimen first-line for some of our patients. I’ve seen the good and the bad. I have seen patients with durable remissions of

two or more years with just these agents who have never had chemotherapy and stage 4 lung cancers, so that’s very unusual. Once the toxicity is managed, people go on to having a normal life. This is a very important advance. Determining who it's right for and how to manage the toxicities is the real challenge for us as oncologists. I don’t think we've ever had a challenge of this breadth and suddenness, but we are pretty resourceful, and I think will learn it.

Dr. Pietanza: One point about the combinations is that they should be still done in the setting of clinical trials, because we need to look at the combinations. Or, at the least, we still need to evaluate the responses, the durations of the responses, and the toxicities.

Dr. Kris: Cathy, have you had some experience in the small cell arena?

Dr. Pietanza: So, we have had patients on both nivo alone and nivo with ipilimumab, and those were presented at ASCO, at World Lung, and at European Cancer Organization (ECCO)/ESMO. The response rates are approximately 20% in nivo alone. They do improve to 30ish—35% with nivo and ipilimumab. It seemed to be a little more durable for the combination, and we haven’t seen, at least in that population, overt toxicities with the combination.7

Dr. Kris: Do you mean new toxicities?

Dr. Pietanza: Yes, new toxicities.

Dr. Kris: I assume though that you have seen colitis, uveitis, rash, the usual?

Dr. Pietanza: Right.

Dr. Langer: But those response rates are impressive.

Dr. Pietanza: For small cell lung cancer, they are very impressive!

Dr. Langer: In the refractory setting, single-agent topotecan has a response rate of maybe 5%, and even in the chemo-sensitive relapse setting, its 15 to 20%, at best.

Dr. Pietanza: Yes, at best. Those are very exciting data.

Dr. Kris: I think another observation not discussed in the abstracts here is the benefit across all the thoracic cancers, small cell lung cancer, and mesothelioma. Corey, let's continue with the next one, another nivo study, getting in a little deeper into this biomarker question.

Nivolumab as a First-Line Monotherapy

Dr. Langer: Biomarker and also safety analysis. This is a trial that looks at 52 patients, both squamous and nonsquamous, with across-the-board responses. They were assessed by the usual means and with PD-L1 testing, and the response rate overall was pretty much what we come to expect—23%. Duration of response, consistent with what we have seen with other studies, was not reached, but it clearly is going to be greater than 1.5 or 2 years, at least amongst those who have responded. Of note, at least in this study, where there were 3 CRs—so even with single agents we are starting to observe that—and the CRs were fairly durable at 41 weeks, and then two that were essentially two years and counting. A number of patients were having these unconventional immune pattern responses where there may have been major reductions in lesions, but there was a simultaneous appearance of other new lesions, often quite small. But, consequently, these patients were not reported as responders. So, in addition to pseudoprogression, we have this apparent dysynchrony that can sometimes occur. Once more, how to manage that both radiographically and clinically is a major challenge and does mandate a new set of criteria in terms of how to deal with these patients. Toxicities were relatively mild—under 20% had grade 3 or 4 adverse events, and not all of these were necessarily attributable. What's intriguing is the relationship between smoking status and time since quitting and response, as we come to see in other trials, particularly in the CheckMate 057 trial where former and current smokers seem to have a survivor benefit but never smokers did not vs docetaxel. We see the same sort of correlation with both response and PFS; current and former smokers ironically do a bit better compared with never smokers. I think that begins to distinguish this class of agents—the immunotherapy approaches—from our typical targeted approaches where those who do benefit the most are the never smokers and remote former smokers, who are more likely to have VEGF family mutations, or ALK or ROS1 translocations.8

Dr. Pietanza: Just to go along with that theme, there was a publication on a series of 37 patients who had been treated with pembrolizumab for NSCLC, and they did a series of analyses. One analysis was for smoking status and that was positive, so patients who had been smokers had better responses. But then they also specifically looked at mutation analyses and found that the patients with higher rates of mutation had a more durable response to the treatment.9

Dr. Langer: The mutation burden?

Dr. Pietanza: Yes, the mutation burden, so above the fewer number of mutations per tumor. So, the patients with higher numbers had a more durable response, and the ones with lower mutation rates had a less durable response. They also looked at smoking signatures, because smokers tend to have transversions. They looked at transversion high vs transversion low, and the transversion high had better responses and more durable responses. In addition, similar to melanoma, they looked at neoantigens, and there were some responses that were better in those patients.9

Dr. Langer: I think the bottom line is that we are semi-obsessed with PD-L1 as our biomarker. There may be many other biomarkers that are just as important, maybe even more important, and more predictive than most of these. Studies have looked at smoking status and divided it into 3 groups: current, never, and former. I think we need a new nuanced assessment of smoking, as this study attempted to do, measuring time since quitting, total smoking exposure, and number of packs per year. As all we know, smoking rates and smoking history might be just as good as PD-L1 testing.

Dr. Kris: I think people are going to start putting these things together. They are going to stay PD-L1–negative and be a never smoker with a very small chance of responding. But as a quick reminder, smoking is a surrogate for mutation burden. Also, those patients who have these oncogenic drivers, especially the critical ones like EGFR or ALK, generally have lower total mutational loads. They are, by that kind of research, less likely to benefit from these agents. The early returns on the treatments for these patients are just that. And just a quick word of caution, this is not the kind of information that one can get from a standard next-generation sequencing (NGS) test. This requires whole exome sequencing, looking at the total number of mutations in an individual patient's tumor. That is not the same thing as counting the number of mutations.

Dr. Langer: So, this goes beyond, say, your typical foundation test?

Dr. Pietanza: Yes.

Dr. Kris: Yes. That said, the more mutations present is a surrogate as well, but it is a surrogate, not like this kind of data using the whole exome. This is moving ahead very quickly. Already, people have been able to perform whole

exome sequencing on blood. This is something we are going to have in our clinics shortly.

Nivolumab and Quality of Life

Dr. Langer: A number of papers were presented at this meeting that focused on the correlation between quality of life and response—in particular, durability or duration of treatment. The first was a symptom analysis and quality-of-life assessment in patients treated with nivo second-line and beyond. This was a large cohort analysis where 557 patients were assessed and included both squamous and nonsquamous, with grade IIIb or IV disease. They looked at lung cancer symptom burden using the Lung Cancer Symptom Scale, as well as EQ-5D visual analog scale, so these are well-vetted, substantiated, validated quality of life assessments that have been integrated into other trials. This is really no surprise; those who responded had an improvement in quality of life. Intriguingly, those with stable disease and the absence of disease progression or verified disease progression, at least for the first 6-18 weeks of assessment, had improvement in some of the visual analog scales. And those who progressed unsurprisingly had a decrement in their quality of life. This is important because we are treating the whole patient, not just the pictures on the scan. If the patient feels better, then the treatment becomes that much more clinically meaningful. I think it's important to at least show these responses we are observing and even stable disease, which reflects the disease control rate, do translate into a quality of life benefit that goes beyond the radiographs.10

Dr. Kris: Cathy, do you have any comments?

Dr. Pietanza: Again, I have a patient with small cell lung cancer on nivolumab who has traveled the world without any of the peripheral neuropathy or other issues we get from other treatments, or diarrhea, etc. So, as Corey said, we are treating the whole patient here. As we’ve said, it's important. The reason for giving patients treatment is so that they can live and have a full life. So maybe these agents are doing just do that—giving patients the full life that they want.

Dr. Langer: It’s an apparent victory if the radiographs improve, but not if they are suffering so many side effects that their lives are not worth living.

Dr. Pietanza: Right.

Dr. Kris: I guess I have to declare a conflict of interest on that trial. I am one of the co-inventors of the Lung Cancer Symptom Scale.

Just a couple of words of caution, though, as you interpret these data. First of all, many people feel that one cannot interpret data in a nonrandomized setting. In the trial that Corey discussed, it was not randomized. The second thing is that there is a huge problem methodologically. What does one do with people who fall off the trial or don’t complete the questionnaire? And who's likely not to? Someone who is ill. And, sadly, the person for whom it is impossible to complete the questionnaire is someone who dies. And one can argue that they have the worst symptoms and generally get excluded. These are tough, tough data. I urge the community, when curing the patient, to give them a durable CR. This issue then goes away, and that's where our thrust needs to be.

Quality of Life

Dr. Langer: In that regard, there are phase 3 data looking at the quality of life and overall health status. The next paper was an analysis assessing that and using EuroQol and other instruments that assess quality of life, as well as the visual analog scale. This was in the context of CheckMate O17, which was the first trial to lead to nivo’s approval in squamous cell in the second line, in comparison with docetaxel. So, some of the criticism you raised is addressed in part in this trial. Without going into the detail of this trial in great extent, the bottom line is that those who were on nivo, at least during the first year of treatment, had their health status improve from baseline during that period, while those on the docetaxel had their health status, at best, remain stable and for a shorter period of treatment. Across the board, not only was there improvement, but it was more durable in the nivo arm. It is critically important that the response rate, PFS, and ultimately OS advantage observed in this trial is translated into a quality-of-life benefit.11

Dr. Kris: Please remember, this trial was not designed as a quality-of-life trial to show an improvement in quality of life; it was designed as a survival-based trial. In essence, this is a convenience sample looking at the quality-of-life endpoint. It's not a prospective trial. I support conducting great quality-of-life research, but they need to be prospective trials.

Dr. Pietanza: This was a secondary, exploratory endpoint setting.

Dr. Kris: Yes, it was a convenience sample, not a prospectively designed trial.

Dr. Langer: But, this is what the patients are experiencing, so it is still quite important.

Dr. Kris: Absolutely, but I bet the patients who have a durable CR are having a good life.

Dr. Langer: I'm sure they are feeling much better, yes.

PDL1 Expression as a Predictive Biomarker

Dr. Pietanza: This next abstract goes again along with the confusion of PD-L1. There were actually two abstracts looking at PD-L1 as a predictive biomarker, and here we are looking at 1 of them. This was a network meta-analysis. In this meta-analysis, they looked for studies that were looking at particularly PD-L1 expression, and they found 83 studies and 79 studies were excluded, so four trials were analyzed with 571 patients. As we've seen in what we've reviewed in this past hour, PD-L1 cutoffs varied along clinical trials. From here, they used as low as 5% to as high as 50%. The overall response rate that they showed was higher with the PD-L1-positive group. This response rate correlated with an improvement in PFS at 6 months, but then not at 1 year. The conclusion of the abstract is that PD-L1 expression is a predictive biomarker for response and maybe for improvement in 6-month PFS, but for some reason in these abstracts and in this meta-analysis, not one-year survival. So I think we are at a loss as to what our best predictive biomarker is.12

Dr. Langer: I think the big issue is that we’re swamped with different biomarkers. There’s a consistent theme across all of the clinical trials, but the randomized phase 3 and earlier phase 1 and phase 2 trials showed that patients who were PD-1-positive do better; they certainly have higher response rates. But as we already pointed out, it may correlate with other issues that you brought up—neoantigen, mutation burden, smoking status. Every single company is using a different assay, using a different cutoff, and looking at different populations. Some are looking at just the tumor cell, others are looking at a combination index that evaluates both the tumor cell and the microenvironment around the tumor. I would call this “biomarker anarchy.” Until we can figure out a consistent way of assessing this that can be expanded and extrapolated to each of the agents, there will remain a lot of confusion.

Dr. Kris: And the reason that the FDA gave approval for nivolumab to be used for adenocarcinomas is because there is a new category of biomarkers—so-called complementary biomarkers. Not a companion diagnostic like with pembrolizumab, but a complementary diagnostic. How would one use PD-L1 testing to help decide whether or not one should use nivolumab?

Dr. Langer: It’s a big quandary for me, and I haven’t sorted this out completely. Right now, in the second-line setting, nivo has a blanket approval for both squamous and nonsquamous. That's independent of the biomarkers, so in a sense that becomes the default agent. On the other hand, by whatever means, I’ve gotten ahold of the Dako kit, and I can look at proportional scores at PD-L1. And if someone is 50% or higher, I’ll likely preferentially treat that person with pembrolizumab. But we have no comparisons between pembro and nivo or pembro and atezo. In that group, I think we are ultimately going to need that, but I doubt the companies want to do that. This is ultimately something that the cooperative groups and individual institutions will probably need to collaborate on. That’s critically important. Right now, I would not be surprised if all the agents were similar in the proportional score. One must remember the proportional score of 50% or higher; pembro’s only applies to about 22%-25% of all patients.

Dr. Kris: Cathy, how does that approval for a complementary diagnostic help you in your selection of nivo?

Dr. Pietanza: I don’t think it would help. I think we've seen data showing that in second-line, the response rates are similar with patients who are treated with docetaxel vs one of these agents. So, in second-line, where I need to give patients something, I’m probably going to choose the agent that's going to cause less toxicity. So I’m going to use one of the newer agents. Obviously, only the two, nivo and pembro, have been approved. Interestingly, as Corey pointed out, for institutions such as ours who either have an NGS or FoundationOne medicine, I’ve used that as a surrogate and when looking at patients with higher mutations, as maybe those patients might have a response. So, I’m going back to the clinical aspects of patients that we used to do with targeted therapies, the clinical characteristics.

Dr. Kris: Yes, that never panned out.

Dr. Pietanza: Right, that never panned out.

Dr. Kris: I have the same issues that you both have. I think where it possibly could be helpful, though, is when one has this on the table as a therapy, and one has a very effective therapy to offer instead. So if one had somebody who had an EGFR mutation, let’s say, and the issue came up, should I give them nivolumab? If they were never a smoker, have a low mutational burden, and were totally negative PD-L1, their chance of responding would be very small. That said, maybe if one had someone who is a smoker with an EGFR mutation and PD-L1 expression in their tumor, it may be helpful. Also with first-line…

Dr. Pietanza: I was just going to say first-line…

Dr. Kris: I think when one has treatments that one knows can be helpful in one-third to a half of patients and one wants to prioritize them, then it might be helpful there, too.

Dr. Langer: I agree, and I think that there will be a lot of studies, as you have pointed out, that will compare chemo to these single agents and probably increasingly the combos of immunotherapies in the first-line setting. And the ones that stand any chance of being positive are those that are in the PD-L1-positive group. PD-L1-negative should probably not be looked at. I think you bring up another very important point—EGFR mutants, those presumably without the ALK translocation, are probably less likely to be PD-L1-positive. But we’ve seen the empiric combination of these agents with TKIs, and I think preferentially going forward, if we are going to do those studies, we should do it in the PD-L1 positive and not necessarily in all comers. And finally, probably most importantly, we want to explore the impact of these agents in the curative settings. Right now, we’ve been talking about stage 4 disease or recurrent disease, and there are ongoing trials. There's the one drug we didn’t talk about, durvalumab, which is being looked at in the phase 3 PACIFIC trial. The trial is randomizing patients with locally advanced disease following chemoradiation to durvalumab vs placebo, and that trial is accruing quite well. There are plans afoot for a very similar trial with nivolumab through the Room to Grow (R2G) Foundation. Of course, there’s the ALCHEMIST trial in the adjuvant setting, which to date has just focused on those patients with molecular markers, EGFR, ALK, which is really the majority of our population—85% or more. There will be a trial coming up assessing PD-1 inhibitors and what looks like now will be nivolumab.

Dr. Kris: Yes, in ECOG, one of our colleagues is spearheading that right now. But I think that you’ve highlighted many of the controversies. Any closing thoughts? We’ve gone through the abstracts we had

selected today. Any comments that you’d like to make, Corey?

Dr. Langer: Just that these are exciting times. When Mark and I started out, we were in the horse-and-buggy era when it came to systemic treatment. Platinum was our best drug. Mark was a big enthusiast for mitomycin C. I can’t think of the last time I’ve prescribed that agent. It’s been roughly 30 years, and we’ve made major headway. And immunotherapy at this point, while not a panacea, is a major era on our therapeutic quiver. It is making a difference; granted, it’s in a select population, a minority. But in that group, it's a robust, significant, clinically meaningful difference, and I think that, in some patients, may be extraordinarily durable.

Dr. Kris: Cathy, do you have some final comments about the data we discussed today?

Dr. Pietanza: I agree with Corey; my career has just started.

Dr. Kris: You weren’t in the horse-and-buggy era.

Dr. Pietanza: No, I wasn’t in the horse-and-buggy era. I didn’t have these agents when I started, but now have them. I agree with Corey. Basically, these drugs are going to be useful for a select population, which we are still trying to figure out. I think the next two years will show many trials looking at how we can make the responses in some of these patients better, but also for the patients who don’t respond, how we can get them to respond. I think the next few years will bring up many more trials with these drugs and combinations with other inhibitors and other targets of the immune cycle. It's going to be very interesting.

Dr. Kris: I think we all agree that we think it's an amazing time to have these additional tools. I do say that it's going to make the job of the oncologist much harder. There are more choices one must make in the course of treatment, and one must be prepared to know when to stop a patient’s agents and, as Corey pointed out, it's often not a very easy decision. We are going to have to be doctors, which is what we signed up for, so that will be a good thing. I also want to reiterate what all the speakers said—we have to keep our eyes on the prize. We have to very quickly look for ways that lead to durable CRs and hopefully even cures for our patients. That's where we need to be, and we need that for every patient. These medications may be another step in that, and we can’t lose our focus on that.

Dr. Pietanza: I just wanted to comment that as we continue to learn about these drugs, there are numerous trials that are ongoing. I think that for all of us involved—oncologist and investigators—that it's very important to put as many patients as we can on clinical trials, even though the drugs are available. I think that if they can come to some setting, some big centers, we should continue to investigate these problems, because we don’t have these issues all sorted out.

Dr. Langer: And these trials ultimately will be available, not just in the academic center, but also broadly in the community, and I think there is much to learn. I agree with you regarding the immunotherapy combinations. But even with the conventional cytotoxics, I’ve been impressed with how easily drugs such as pembro combine with pemetrexed and carboplatin. It remains to be seen how effectively, but so far the signals are quite impressive.

Dr. Kris: And with that, I would like to thank my colleagues today, Corey Langer and Cathy Pietanza, for talking about the exciting developments that came out of the ECC this year. Thank you for joining us today, and I hope you found this CME program interesting and that it will help you make some better decisions for your patients with these illnesses.

Dr. Pietanza: Thank you.

References

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