Introduction

DR LOVE: I’m Neil Love from Research To Practice and welcome to Meet The Professor, as today we talk about the use of immunotherapy in the management of lung cancer with Dr Stephen Liu from the Georgetown University Hospital in Washington, DC.

As always, we have some cases from the field, so to speak. To present, we have 4 general medical oncologists as well as Dr Matt Gubens, a lung cancer investigator. They’ll be presenting cases. These other oncologists, general oncologists, they sit down with me for an hour or an hour and a half, we present CLL, myeloma, lung cancer, bladder cancer. They have got to stay up on everything. And everything is — so much is going on.

So we’re going to start out today, before we get to the cases, of course, I’ve got to ask Dr Liu if we’re talking about immunotherapy, about the monstrous, huge, gigantic ASCO meeting this year where 2 huge presentations came out, the IMpower study of adjuvant IO, atezolizumab and the neoadjuvant trial looking at nivo plus chemotherapy. We’ll get to that in a second and then we’ll get into cases and then we’ll kind of talk a little bit about where things might be heading in the future.

Adjuvant and Neoadjuvant Immunotherapy for Non-Small Cell Lung Cancer (NSCLC)

DR LOVE: But the first thing I want to just bring out, Stephen, is the fact that, you know, in lung cancer, we have these 2 so very, very important trials we have to consider, but there’s a lot going on in the adjuvant space nowadays in oncology. In breast cancer, we just had the adjuvant abema approval. Everybody’s trying to figure that out. We saw the olaparib data from the OlympiA study. I would imagine that’s going to get approved soon. Pembro just got approved in triple-negative disease. We’ve had T-DM1 already out there in the post-neoadjuvant setting. Upper GI cancer, GU cancers, ovarian cancer the last couple years, PARP inhibitors. There’s a lot going on in the adjuvant space and a lot of the principals that we’re going to be talking about today, I think really carry over.

So, Stephen, let’s just start out and talk about the data that came out. As I mentioned, atezo just was approved in the middle of October based on the IMpower010 study comparing atezolizumab after chemotherapy. We saw a nice impact on disease free survival there with a hazard rate of 0.66. Here are some of the other points that came out in the trial in terms of the impact. But also, they looked at PD-1 status and it looked like the patients who are PD-1 negative didn’t really benefit and, in fact, that was the approval. So before we go on, Stephen, maybe if you can just comment a little bit about this study. Anything you want to comment on? And particularly, the safety data, I think, was kind of what we were expecting. How have you been processing this? And how has it been discussed in your Tumor Board since that time, Stephen?

DR LIU: Well, Neil, we’ve been pretty much all in on the use of adjuvant atezolizumab already. Really, even using it before the FDA approval recently, after we saw that initial ASCO presentation from Dr Heather Wakelee. Those hazard ratios, I think, are quite impressive. When we look at the use of adjuvant atezolizumab after adjuvant platinum-based chemotherapy for PD-L1 high, a hazard ratio of 0.43 for disease free survival, I think more than justifies the use of what I think is a very well-tolerated regimen in that setting.

DR LOVE: Of course, and all of these trials, a lot of — when trials first come out in the adjuvant setting and most of the trials that we were talking about that had data in the last 6 months, you just have disease free survival as you do right now for IMpower. And that brings up — and we talked about this last year when osimertinib came out with that incredible hazard rate for progression, but yet, we’re still waiting for survival and whether you treat or not when you don’t have survival. And, again, this kind of crosses lines. It’s interesting when you ask Heather because Heather was kind of lukewarm about osimertinib in the beginning because, you know, she said well the curves come together, but she’s way more positive about IO. And she uses actually the PACIFIC trial as an example and the fact that the PACIFIC trial, we have long follow-up. And thoughts about that as a motivation to buy into just disease free survival at this point, Stephen?

DR LIU: These are great points. I think they’re 2 different strategies. When you look at osimertinib, those curves are very wide apart, clear separation. And the question is, will those come together over time? Are you preventing recurrence or are you just delaying it until later? And I think that’s a valid argument though the FDA would say that there’s value in DFS in and of itself and I agree with that statement. But I think that Heather is making a point that’s very valid that immunotherapy does lead to more cures. TKI doesn’t really cure patients. Immunotherapy does. And so by introducing that into resectable lung cancer where our outcomes are not as good as other cancers where the relapse rates are still quite high, I do think we will see more cures. And so I think the data are very exciting.

DR LOVE: So and, of course, you have to balance out the toxicity because, you know, less toxicity, you maybe you put up with less benefit. Actually, the other thing is, you were talking about disease free survival, one of the things that I personally was really impressed with, I know a lot of other people with the osi data, was brain mets, you know, 10% versus 1%. Just that benefit by itself seemed like it was, particularly for a drug that’s pretty well-tolerated.

So the other data set that came out — it’s interesting, I talk to general oncologists every day and most of them have heard about the atezo paper and a lot of them have not heard about this neoadjuvant nivo study which I thought was incredible really. So in any event, CheckMate 816. We saw the data at ASCO, we’ll show that. But just in the last couple days, we saw this press release saying there’s a disease free survival benefit to neoadjuvant chemo/IO, so nivolumab. So we’ll see when that gets presented, probably, I guess, next year. Who knows? AACR, ASCO, et cetera. But these are the data we started out with, Stephen, in the 816 study. Can you talk a little bit the entry criteria and what they looked at here?

DR LIU: Well it’s including Stage IB to IIIA resectable. That’s an important point. This is not looked at as a conversion therapy as someone that is unresectable or borderline resectable, to use this therapy to get to resection. While that is an interesting strategy, it’s not what this study was. This was upfront resectable and then neoadjuvant chemotherapy for 3 cycles or chemotherapy with nivolumab. Originally, there was an arm with nivo/ipi, but really the focus here is on nivo/chemo. And what we saw was a striking increase in pathologic CR rate where there is no tumor present.

These numbers are quite different, 2% with chemotherapy, 24% with immunotherapy and chemotherapy, a really high rate where there’s just no tumor left. And what we see is dramatic responses, as you can see from this plot, huge pathologic regressions. At the time these data were presented, we didn’t know if that would translate to a clinical endpoint, to event free survival. The nice thing about pathCR is you know it the day after surgery. Our pathologist tells us that right away. And so if that correlates to clinical outcomes, that’ll be a very powerful surrogate. We now saw from that press release that it does increase event free survival. And there are multiple studies that have shown us pathologic CR rate does correlate with long-term outcomes. I know that we still need to sort of show it in this trial and we’ll wait for OS, but I do think these data are practice changing.

DR LOVE: I guess, you know, again, if you think back to breast cancer, they eventually evolved into a paradigm that you kind of see the same thing long-term whether you give chemo or whatever before or after surgery. I don’t know if we have that much data in lung cancer at this point, but in any event. The other thing that was really fascinating is it looked like it affected the kind of surgery that people had, whether they had pneumonectomy, et cetera. I thought that was incredible. Any thoughts? I thought it was worth doing just based on that without the disease free survival.

DR LIU: Yeah. It makes sense. And initially, that was our concern. We’re giving immunotherapy upfront and there have been these whispers over the years that immunotherapy seems to increase the perihilar fibrosis and maybe it’s making the surgeries a little more complicated similar to what we had said years ago with radiation, that giving this therapy upfront seems to make the job of the surgeon harder, maybe there’s more complications. But they looked at surgical outcomes here. In fact, a lot of the investigators on that study were surgeons. And what we saw was every surgical outcome was better with immunotherapy. There were fewer open conversions. There were fewer complications postoperatively. And the duration of surgery, the time of surgery, was shorter with immunotherapy. Across the board, better outcomes. And the way I explain it now is that if your cancer is gone, which is what happened in 24% of the patients, surgery is a little bit easier.

DR LOVE: So yeah. And, again, you see that in breast cancer, women who can’t have breast conservation, they get neoadjuvant therapy, then they can, the axilla more likely to be clear. So not a huge surprise. So let’s start to piece together what this all means. And we actually have a good case that I think is going to really help tease out how you view this. But I want to just start with a — let’s start with a straightforward situation of an adjuvant situation. I think the neoadjuvant thing maybe is going to evolve over time, particularly as people see this new data. But for now, we’ve got the adjuvant data, we’ve got an approval and, you know, it’s time to talk about what to do here. And, you know, our history, Stephen, as a CME group, we’ve been talking about adjuvant therapy — that’s how we started as a CME group was adjuvant tamoxifen, believe it or not. But one of the things that happened over the years in breast cancer and oncology in general, and a lot of this was because of the adjuvant online model that Peter Rubin, who we worked with a lot developed.

And, of course, that’s no longer available for the newbies, so to speak. That was an online model that gave you numbers. It didn’t tell you how to treat, it just gave you numbers. And so we have been applying that concept in general, in breast cancer, and starting to bring it into other cancers. So we wanted to do a little experiment with you and the audience tonight and try to get some numbers from you. And the way we positioned this — and we did a big project focusing on HER2-positive breast cancer a couple years ago where we asked a bunch of investigators, okay imagine you’ve got a patient who wants some numbers, maybe they’re a medical oncologist, who knows, they have some medical background, but they would like your best estimate knowing that we don’t know everything, your best estimate of the numbers. And so we asked you, Stephen, and we’re asking the other faculty, what you would say to a patient who has either Stage IB, IIA, IIB or IIIA disease. We said we’re going to say it’s a 65-year-old person and we’re going to say the TPS is 50% just so it’s positive. That’s just the first case we’re going to present. So the first thing we said was, okay for these 4 stages, roughly, what would you say if you gave them no adjuvant therapy, the chance for relapse is?

And that’s your first column there. And, audience, you can look at that and see if those are the numbers you’re giving your patients. Then, we said, okay well what about adjuvant chemo? If it were used, we aren’t saying you should or shouldn’t, but if it were used, can you give us an estimate of the impact? And, of course, I guess, globally, we think about a hazard rate of maybe 0.88 or something with chemo, Stephen?

DR LIU: Yeah, globally, but there are a lot of variables in there and remember that a lot of the data, a lot of the tables that we’ve become so familiar with are using an older staging system. And so now that we moved into AJCC 8^th, what we used to think of as a IB, probably is more like a Stage II now in most cases. But generally, I would think that the benefit of chemotherapy primarily driven in the adjuvant setting for Stage II/III.

DR LOVE: So and that’s reflected in your numbers here. But now what we added in there is, what about adjuvant PD-1, specifically, atezo? And so we said, okay you have a patient who is IB, you’re saying if you give them chemotherapy, it’s really not going to change much or at all, but what about if you added in atezo after the chemotherapy? And you say that your best estimate is the relapse rate would come down 5%. I guess thinking about a hazard rate of, you know, 0.7 or maybe even a little better than that.

So a 5% absolute benefit. We asked you, what treatment you generally would use in this situation. You said none. We’ll get into that in a second. But for the other scenarios in a PD-1 positive patient, you said you would use chemo followed by IO. And, of course, the benefit, the absolute benefit because the hazard rate chemo, 0.88 or maybe it’s better than that, but not a whole lot better. Actually, better hazard rate by adding in the atezo, right?

DR LIU: Yes. Yes. Absolutely.

DR LOVE: Get more of a kick out of the atezo than you get out of the chemo. And then, I’m going to ask you a question. I was curious, I’ve been thinking about this all night how you’re going to answer it which is, again, you’ve got a patient, they’re a medical oncologist, they know all this stuff and they say, well what do you think, you’re telling me I’ve got Stage IB disease, chemo is not going to give me much of a benefit, I’ve got about a 1 in 4 chance of relapsing, how about if I just take atezo? Would you give that person a number? Do you think you could come up with a number?

DR LIU: Well I think that the benefit in that setting — the real answer is we don’t know, right? Because while IMpower010 did include Stage IB, those would be considered Stage II now. And the Stage IB here, the risk is lower. It is greater than other cancer types. That’s true. And if we’re looking at numbers of relapse, I would agree that for a Stage IB, the rate of relapse is probably unacceptably high considering it’s still a Stage I tumor. I don’t know how much atezo drops that risk and I don’t know if the toxicity and the cost associated with it really justify its use there. So you’re operating a little outside of the data. And, you know, there’s the potential to do harm with these. So for a Stage II/III where we have strong data, I am all in. And while the data for the PD-L1 high, I think is fantastic. Hazard ratio there of 0.43. If they’re ultrahigh, probably even higher. But even for the low, for PD-L1 low, I think that it’s a very reasonable option and I’m probably recommending it even for my PD-L1 low driver wild type. For a Stage I, I think that there’s the risk I could be doing harm there and so I really need to think carefully there.

DR LOVE: So just out of curiosity, again, for your Stage II and III patients, if they said, how about just give me atezo, would you be okay with that?

DR LIU: Well first, I would try to figure out why they don’t want chemotherapy. And if it’s a lot of sort of the mythos of chemotherapy, I’d try to dispel that because, I hope I don’t sound boastful here, Neil, but I think I’m pretty good at giving chemotherapy and even a few cycles. And if we look at the study, most patients received all 4 cycles of chemotherapy in these trials. And so I would try to deliver it, understand what the fear is there and really reinforce that that is a proven OS benefit, not a DFS benefit. So to me, it’s really an and, not an or. And I’d really try to get some chemotherapy in.

DR LOVE: So, audience, I want to know, how long have you been in oncology practice? I think most of the people online are in oncology practice. And it’s interesting because we know we have a significant fraction of our population is millennials, you know, under age 40. And here, it looks like one-third of the audience have been in practice less than 10 years. So I’d say they’re probably millennials, under age 40. But then we have docs who’ve been in practice 20 to 30 years.

Almost one-third of this audience has been in practice more than 30 years. So we’ve got a wide spectrum of age here. And, of course, what that means is — because there’s another disease we all have, it’s called just being a human being and, you know, dying of old age if you can get to that point. And so, you know, the adjuvant online actually gave you the risk of noncancer mortality to consider. So when you have a patient with Stage I breast cancer and they’re 90 and you look at their 5-year survival from being age 90, that’s really the threat in that situation. So we’ll keep that as background that the audience has a spectrum of responses.

But, audience, here’s what I want to know from you.

You’ve got Stage IB non-small cell lung cancer, the TPS is 50%, you just heard Dr Liu describe what he would recommend which is nothing. And so we’d like to know, what do you think you might do in this situation if it were you at the age that you currently are? And I’d say about 30% of the audience agrees with you, but the rest say, if it were me, most of them — well they’re kind of split between chemo/atezo and atezo alone. The most common answer is chemo/atezo. And if you look back at the numbers you gave, you know, there is — you do say there’s a benefit. Let’s say 1 out of 20 chance you’re going to avoid recurrence.

On the other hand, you can say, I don’t know. What would you say if the same person said to you, what’s the chance I’m going to have a serious IO problem like type 1 diabetes or colitis or pneumonitis?

DR LIU: It’s probably — it takes a little bit away from that because it’s a non-zero number. And so there is a risk that you could have a complication. And, you know, do no harm here. There’s an unknown benefit. There is a clear risk. And so in settings like that where the margin for benefit is pretty slim, I really worry about tipping the scales in the other direction. Toxicity, severe ones, are fortunately uncommon. I think we’ve all seen a couple. And wouldn’t it be a shame if you had someone that was probably already cured, you gave them immunotherapy and really changed their life for the worse. That’s something you really need to pause and think about.

DR LOVE: So, you know, so many complicated decisions now in oncology. It’s always been the case. That’s what we do, so to speak. Just a couple other things, then we’re going to get into cases. We asked a couple other questions in this survey, Stephen. One was, in what situations right now, I probably should have said put aside reimbursement issues, would you generally be thinking about neoadjuvant chemotherapy, whether you’re going to add in an IO or nivo or not? Right now, when are you thinking about neoadjuvant therapy? And do you think your bar for neoadjuvant is going to change?

DR LIU: That’s a good question. I think that it is an evolving space and I think we’re all not satisfied with how we’re treating our Stage III patients. We know that in many cases, earlier stage, surgery is really the best modality in terms of appropriating a cure and I think that is still the case for a Stage III. And so if someone has a resectable Stage III, I don’t do chemoradiation, I really try to get them to surgery. I think there’s value in that. The randomized data, overall, the intergroup study, a negative trial from Dr Kathy Albain, a negative study looking at tri-modality therapy, but in the subset of patients that did not require a right pneumonectomy, we saw clear separation of those curves. Those are old data. I don’t know if we’re going to have newer data in that area, but I think there’s value for surgery as long as it’s not bulky N2 disease, as long as there’s not N3 disease. If it’s microscopic, modestly sized N2, we will start with neoadjuvant therapy and my goal there is to try to get them to surgery.

DR LOVE: So I’ll be really interested in the feedback from the audience about what you think about this approach to trying to tackle this problem. It’s going to take a while. So much to talk about here to get into the granularity of these complex, but really important decisions. I’ll tell you, here’s my fantasy, Stephen. I don’t know if you’ve ever seen this. There used to be a conference called Adjuvant Treatment of Cancer. Syd Salmon, a doc who started this, I think, I don’t know, 40 years ago. Well it was a book. They would actually publish the book. They didn’t have people come from all over the country to Arizona. Breast, melanoma, et cetera. So that’s my fantasy. I want to do another adjuvant conference and talk about lung and upper GI, et cetera.

Case: A man in his late 50s with metastatic NSCLC and no actionable mutations — Sandip Patel, MD

DR LOVE: But let’s get into some cases. And actually, we’ll start out with metastatic disease just to take a breather from localized disease. And we’re going to start out with a patient of Dr Sandip Patel. He has a patient that had a very interesting experience that you hear a lot about, but I don’t hear too many cases of. I was curious what your thoughts were. This is a 57-year-old man with metastatic disease who got chemoimmunotherapy and kind of an interesting experience as a result. I believe this was carbo/pem/pem. Here’s Dr Patel.

DR PATEL: This is a 57-year-old patient who I actually just saw and has a diagnosis of metastatic non-small cell lung cancer. No actionable driver mutations. On baseline oxygen from their COPD. Starts chemoimmunotherapy and has a decrease in their oxygen requirement, is actually starting to gain lean muscle mass, says they’re feeling stronger, they’re getting out of the chair a little easier in clinic within 6 weeks of starting chemoimmunotherapy. However, their CAT scan shows almost a 50% increase in the size of multiple mediastinal lymph nodes in the chest. And so we were left with what to do in this scenario in which clinically, the patient seems to be doing well, but the CAT scan seems to show a substantial worsening of the lymph node predominant disease. Because the patient was feeling so well, I suggested, hey let’s just do another scan in 6 to 8 weeks. If you’re not feeling well, please let me know. And so we continued them on their therapy. We got a repeat scan and those lymph nodes that had blossomed, unfortunately, to 50% increase on initial scan, actually had shrunk 50% from their baseline when we saw the patient in subsequent imaging.

DR LOVE: So I’m not sure what you call this. He called it, when I was talking to him, he said, I think this is “pseudoprogression”. I don’t know exactly what you call it. But what I want to know is, what happened? Like what’s going on?

DR LIU: So to the best of our understanding when we see these atypical responses, when we see this pseudoprogression, in a good sense, it is really the immunotherapy having the desired effect. So if we’re watching a tumor, we give a checkpoint inhibitor, those lymphocytes are now recognizing that tumor and when they become activated, they will undergo clonal expansion, they will make a lot of copies of themselves and now you have this army of lymphocytes that’s infiltrating and attacking that tumor. And as they infiltrate that tumor, they take up space and so it stands to reason that that lymph node, that tumor, that nodule may get a little bit larger transiently and as the effect continues, then we’ll see it shrink. And so in theory, you could see a tumor at baseline, treatment starts working, white cells come in, it gets a little bit larger on CT scan, if you took a biopsy at that point, maybe you’re not seeing tumor cells proliferate, maybe you’re not seeing a lot of mitoses, maybe you’re just seeing a lot of lymphocytes and then with a little more time, you can see a drop. And so that initial swell, we often will call pseudoprogression. There are a lot of terms for it. What I can tell you, Neil, is that it makes a nice story, it is not nearly as common in lung cancer as it is in other cancers.

DR LOVE: So yeah. I’ve heard that description before, but I always had another model in my mind and I want you to tell me whether you think this might be an explanation which is, it just took a while for immunotherapy to start working and actually the reason these things were getting bigger was it literally was progressing, but let’s just say it took a few months for the immunotherapy to start working. We know you can see delayed immunotoxicity. So why can’t this be delayed efficacy?

DR LIU: Yeah. It absolutely could. Generally, the sense is that for some cases of pseudoprogression, I think there are a lot of different scenarios where that situation can occur and I think in some situations, if patients are clinically feeling better, starting to gain weight, having some positive effect, generally, you think that it’s having some antitumor at that point. So if they notice a clear improvement clinically after a few doses and then you still see a rise, that might suggest that it may be the immune infiltrates accounting for some of the size, but there’s probably both things happening.

DR LOVE: Yeah. Well I remember when IOs started to come out of melanoma and into the rest of the world, the melanoma paradigm always was, if the patient’s doing good, keep going. Just focus on how the patient’s doing.

DR LIU: And in some settings, it really reflects the lack of other great options, but when we’re seeing what a difference maker checkpoint inhibitors can be, we’ve learned that we don’t want to give up on them too early. That this really could be something that’s going to give us long-term benefit. We wouldn’t want to throw that away sort of at something that may not be definite.

DR LOVE: Incidentally, any sort of hypotheses on what’s going on when you see delayed immune toxicity? A year later, you see LFTs or colitis, et cetera. Any theories about why that pops up a year later? Do you think maybe coincident, you know, events are affecting it?

DR LIU: I do think that’s the case. I think that while we have a lot of elegant studies and that can show you lots of sort of preclinical data, between you and me, we don’t totally know why these drugs work in some people and don’t work in others, right? The immune system is a very complex machine and there’s a lot of sources of input and I think it works both ways. Late toxicity, what happened that allowed that lymphocyte that’s going to interact with that colonic crypt cell to activate? But I’ve also seen a couple cases of late response where we’ve had a minor response in stability for a year and then all of a sudden, tumor starts decreasing, we get a major PR, patient asks sort of, what happened, what did we do? And I sort of shrug my shoulders and I don’t know.

DR LOVE: Wow. I never heard of those. Maybe it’s the vaccine, just kidding. But anyhow.

DR LIU: Positive thinking.

DR LOVE: Yeah. Okay. Another question we asked in the survey, we’re going to talk a little bit more about metastatic disease. One of the real challenging questions is in TPS of 0. So you say, in general, when you use carbo/pem/pem with a TPS of 0 in adeno, but what I thought was interesting is you say you use ipi/nivo + chemo with TPS of 0 when squamous. So what’s your thinking there?

DR LIU: Well I’ve been a little disappointed with the performance of our standard chemo/IO options in squamous lung cancer. And to me, this remains an area where we could do a lot better. For squamous lung cancer, while there is clear benefit to the addition of pembrolizumab to carbo/pac, to carbo/nab-pac, the degree of benefit and the durability of that benefit, I think is a little bit less impressive than we see in the non-squamous histology. What I thought was most impressive about some of the CheckMate studies, including CheckMate 227, was how it performed in that PD-L1 negative group, and you do see benefit in squams. And if reimbursement was not an issue, Neil, in the right patient, I might think about just nivo/ipi in this setting. Now in my own practice, I have a lot of patients that have Medicare, if I try to give nivo/ipi, I run the risk of that patient being stuck with the bill for off label use in PD-L1 0%. So the CheckMate 9LA regimen with just 2 cycles, limited chemotherapy, plus nivo/ipi long-term is an FDA approved regimen for a squamous PD-L1 0% and it allows me to use that nivo/ipi long-term and it really is just a dissatisfaction with the standard approach and the outcomes we have in squamous lung cancer.  

Case: A woman in her mid-60s with newly diagnosed adenocarcinoma of the lung — PD-L1 65% — Raji Shameem, MD

DR LOVE: Okay. Let’s go to another case. And this is a patient of Dr Raji Shameem. A 66-year-old woman, a patient with adenocarcinoma, metastatic adenocarcinoma, PD-L1 of 65%. The patient was a never smoker, presented with progressive shortness of breath, was pretty sick by the time she had treatment. He really wanted to start treatment, but he didn’t have the NGS back. Here’s Dr Shameem.

DR SHAMEEM: She was pretty symptomatic. Persistent O2 requirements. I recommended frontline systemic therapy with carboplatin plus pemetrexed and pembrolizumab, however, with her never smoking status, I was thinking she would have a targetable mutation. I held pembrolizumab cycle 1. She had an amazing response to the treatment, the chemotherapy, decreased O2 requirements, improved functional status, she did well. Liquid NGS testing came back about 8, 9 days after doing it. What I noticed was the NTRK mutation, NTRK3. I got her tumor tissue NGS, notable for PD-L1 65% TPS and also noted was that NTRK fusion was reported to be negative. So there I was and I had the patient, you know, I started treatment. She was doing well, so I wanted to continue on my current regimen. I added pembrolizumab cycle 2. I felt reassured that her PD-L1 was elevated, it was the right thing to do. She’s had restaging scans and show a continuous response, reduction in size of the right hilar lung mass and no recurrent pleural effusion. She’s currently on maintenance pembrolizumab and doing really well. The question I would have, which agent would they typically use, entrectinib or larotrectinib? Is there any data that one would have better CNS activity? Because I worry about risk for CNS metastases.

DR LOVE: So in addition to those 37 teaching points, I’m going to throw in 1 other question for you which is, what would you expect out of IOs with NTRK? We have concerns and data with EGFR and, you know, maybe ALK, but when you get into these rare ones, how do you think about IOs? But let’s just start out with the initial management. This strategy that he used by holding off on the IO, any thoughts about that? Would you do it even on a smoker?

DR LIU: Yes, I would. And it’s very sophisticated. And, Neil, I’ve got to give you credit here because you’ve been preaching this from day 1.

DR LOVE: I’ve been harping on it.

DR LIU: Yeah. And it’s a really important point because if we did find that in EGFR and ALK, we know we’ve got effective drugs there. We want to go towards that. And if you give a dose of pembro before that, you can’t walk back from that. It’s a lot more toxic, it’s potentially dangerous. And so giving that chemotherapy upfront until you have the full NGS, a very smart decision. Also, very smart to, you know, someone who’s symptomatic where the pace of disease is sort of begging for action, not to just wait because lung cancer is an unforgiving disease. So I love what he did there. I think that’s very sophisticated. I think that’s the absolute appropriate thing to do. When you get those results back, I would say that I probably would have gone after the NTRK, that I probably would have said, all right, we have the chemotherapy. You know what? We’re going to put this in our pocket. And I’ve had very good results with upfront frontline NRTK inhibition. I just saw someone today, Neil, 4 years on their NRTK inhibitor.

DR LOVE: Wow.

DR LIU: 4 very high quality years and, you know, we’ve still got chemotherapy in our pocket to this day and I’m hoping that that’s where it stays.

DR LOVE: You know, it’s amazing. We talk to investigators and go, oh yeah, we used erdafitinib, this, this and this and then you go to general oncologists and say, have you ever used erdafitinib? They go, no. And they’re waiting for their first patient and they’ve got to be ready. They’ve got to be ready for every one of these things and maybe they’ve never used it. What about the question of choice of NTRK agent? CNS penetration? And my question about IOs in people with NTRK?

DR LIU: Okay. So entrectinib, larotrectinib, both good drugs, very high response rates and I think pretty comparable. You’ll notice that the data when you look at the different datasets, some points better and some points worse than others. Overall, I really think they’re the same. And a lot of the difference has to do with how the studies were done, the types of patients included. In my mind, they’re both very effective drugs. Most of the toxicities are going to be related to blocking NTRK. NTRK is responsible for proprioception, for appetite, for pain. And so when you block that, that’s where a lot of the side effects are. That’s going to be independent of how you’re blocking it.

So to me, they’re both very similar. I’m probably going with whatever the insurance is going to be easier for. I think that entrectinib probably does have a slight edge for CNS, at least on paper, but both drugs are active in the CNS. So I really think you can’t go wrong. Your point about IO is a tough one. We don’t have the right answer to it. Generally, if we look at the IMMUNOTARGET study from Dr Julien Mazieres, most of the driver alterations, especially the fusions, generally, the response rates to IO are low. Exceptions for drivers would be things like MET, BRAF, certainly KRAS, but most of the fusions, your response to IO alone is low and so I don’t think it’s wrong to add the immunotherapy as Dr Shameem did. I think that I probably would not expect much out of the IO. And if you’re going to ask, you know, what about giving NTRK after IO? Is it more toxic? We don’t know. I don’t know if we’ll ever know because it's so rare.

DR LOVE: So you mentioned BRAF and, of course, there, you see more smokers. When you try to think about this question of whether or not an IO is going to be helpful, do you also consider the smoking status? If you have a smoker with BRAF, are you more likely to think about an IO?

DR LIU: Neil, my fellows are going to think you’re sitting in my clinic. That’s exactly what I look at. So in my BRAF V600E, there’s 2 flavors. There really are patients that have a long smoking history, have a BRAF V600E and those that have never smoked. And I do think that those are phenotypically different. I think they’re biologically different. And I do approach them a little different.

NTRK3 is unique and, you know, if we’re looking at fusions, and it’s fusions, not mutations. If we’re looking at fusions, NTRK3 is a little different from NTRK1 and 2 because NTRK3 is a very long gene with a lot of noncoding genes and so in tissue testing, if your next gen sequencing is DNA-based, you’re going to miss almost all NTRK3s. You really want RNA-based sequencing. And so when you’re finding an NTRK fusion, you’re likely to miss NTRK3 in particular if you’re doing DNA-based NGS.

DR LOVE: That sounds like a good boards question. All right. Let’s go on.

Case: A man in his early 70s with localized NSCLC and no actionable mutations — PD-L1 90% — Kapisthalam (KS) Kumar, MD

DR LOVE: Now, we’re going to get to our adjuvant/neoadjuvant case. This is a 70-year-old man, a patient of Dr KS Kumar. This is a patient with localized adenocarcinoma, PD-1 of 90%. However, it was abutting the mediastinum and this is actually in the pre-ASCO days, but not that long ago. The surgeon said, you know, I’d like you to give some neoadjuvant therapy, pull it away from the mediastinum a little bit. Here’s Dr Kumar.

DR KUMAR: The surgeon felt he was unresectable very close to the mediastinum, the left upper lobe mass. So he recommended that I give neoadjuvant chemotherapy. Restaging PET scan showed a good response to chemotherapy, so he underwent surgical resection. All nodes were negative and the residual tumor was 0.6 cm. His PD-L1 was 90%. Just after he completed the surgery and follow-up, at that time, IMpower010 came out and even though he didn’t fit the correct situation, I was wondering whether he would be a candidate for PD-L1 therapy. So for the faculty, even though he does not fit the criteria for the IMpower010, is it reasonable to give anti-PD-L1 therapy for this patient? And if I had seen the patient initially and known the results of the neoadjuvant anti-PD-L1 therapy for non-small cell lung cancer patients, could we have considered that if we had known his PD-L1 90%?

DR LOVE: I was just thinking how similar this is to triple-negative breast cancer, believe it or not, but we’ll talk about that another time. But really similar kind of paradigm. Okay. So what are your thoughts about this case?

What would you do if this patient showed up today in that situation? What would you do now? Would you try atezolizumab in this situation? Any other thoughts about this case?

DR LIU: Well kudos to Dr Kumar. I think that this is exactly the right question. This is the art of medicine, that we never have a dataset that perfectly encapsulates the patient that’s in front of us. That doesn’t exist. That’s not how our clinics work. That’s not how my clinics work. And so in this case, we give neoadjuvant therapy, we get a major pathologic response, not a PCR, but a major pathologic response in a high PD-L1, ultra-high, at 90%. I absolutely would offer atezolizumab in this setting. And I know it doesn’t perfectly match that, but when I think of the science here, I see no reason why this person wouldn’t derive the same benefit here.

So, yes, I would offer 1 year of adjuvant atezolizumab giving 1,680 mg monthly to this patient. If I saw this patient upfront, would I add atezolizumab in the neoadjuvant setting? Would I add nivolumab rather with chemotherapy as a neoadjuvant treatment? I do think that’s pretty reasonable. It is not yet FDA approved. So, again, depending on you pairs, depending on insurance authorizations, costs, I don’t want patients to get stuck with the bill, we have a good adjuvant setting, but I do think neoadjuvant use here is reasonable and hopefully will be approved lately, but one big caveat, Neil, and this is where we’re going to have to change our practice, I would only offer neoadjuvant therapy, and in this case, I would only offer adjuvant therapy, if there were no drivers. And so we’ve got to test them for drivers because if I’m seeing EGFR, I’m going a completely different route.

Case: A woman in her early 60s with extensive-stage small cell lung cancer — Ranju Gupta, MD

DR LOVE: Let’s flip over and talk a little bit about small cell. We have a case from Dr Ranju Gupta who has a 60-year-old woman with extensive stage disease. Here’s Dr Gupta.

DR GUPTA: We gave her the standard treatment with 4 cycles of carboplatin, etoposide and atezolizumab. She did very well. Very good response to the treatment. And now, she’s on maintenance atezolizumab. So she’s doing well. She has not had any autoimmune toxicity from the atezolizumab. So my question here is, when she has progression of disease, and today with some of the newer medications and the fact that she’s already received immunotherapy in first line, what are the second line treatment options available? At one time, we were doing prophylactic cranial irradiation in extensive stage small cell lung cancer if they had stable disease overall and then the trials showed that there was not much benefit of doing that in extensive stage small cell lung cancer. Now with immunotherapy and a little bit better responses, just to kind of have a discussion and refocus, would there be any role of PCI if patient has stable disease, say for 6 months or more?

DR LOVE: So any thoughts on PCI? Also, choice of IO? We have both atezo and durva. Most people think it’s kind of a letrozole, anastrozole coin flip thing, you can’t tell a difference. Is that the way you see it?

DR LIU: It is. I think that they are more similar than different. I think that, you know, atezolizumab was approved first. That’s the drug that I have a little more comfort with, a little more experience with and so that’s what we’re using at Georgetown. Durvalumab, absolutely appropriate option. Both of those curves look the same. The way I look at it, those 2 studies, IMpower133 and CASPIAN, really reinforce each other. If 1 was positive and 1 was negative, you would kind of raise your eyes and really wonder if it was real, but because they both got almost identical results, I really think they are pretty interchangeable. The question of PCI is a real good one. And this is one that we come across lately. I always discuss it with my patients. I always discuss it, but I say, we have not done PCI in my small cell lung cancer clinic here in several years.

And the data that she’s talking about were the Takahashi data. Remember the PCI decreases the risk of brain metastases, we know that. But early studies, the Auperin meta-analysis, the Ben Slotman study in The New England Journal of Medicine showed that it also improved survival. And survival gains in small cell are hard to come by and so any little benefit, we were seeking out. But those are pretty old studies and the big critique against that Slotman trial is it was before MRIs and so we don’t know if patients had brain metastases to start with. So they replicated that trial almost exactly except adding MRIs at screening and in surveillance, that was the Takahashi data, and that showed decrease in brain mets, yes, difference in survival, no. And so with no difference in survival and having seen firsthand the cost of sort of long-term neurocognitive benefits, PCI has really no place in my clinic now. There’s an ongoing study, the MAVERICK study, that’s relooking at that question here in the US and that’ll give us a more definitive answer, but the answer to your question, Neil, no, I do not use PCI.

DR LOVE: So another question is, why don’t we see more benefit from IOs in small cell? It kind of seems like, you know, a lot of mutations, I don’t know, heavy smoking. Just sort of intuitively, you would expect it. It kind of seems like moderately helpful, but not like a homerun. And my question is, why? I had the same question about cervix, cancer of the cervix, because the initial study with pembro was like not that exciting, but then, the cemiplimab study came along and now more recently, the pembro first line and okay, it’s up there with lung cancer non-small cell. Why don’t we see more benefit with small cell, Stephen?

DR LIU: Yeah. What a great question. So as you remember, I was one of the PIs for the IMpower133 trial and going in, we had all the hopes in the world for the reasons you exactly stated. It’s a cancer, you know, a carcinogen-associated cancer, smoking rates, very high mutational rate. We thought this was going to be a homerun. I thought the curves here were going to look like the ALEX curves, right? And when they first showed the survival curves, when we look at that a little before those data were released, just among the steering committee, I will admit that my first reaction was a little bit of disappointment, that I really wanted these widely split survival curves.

As you sort of digest that data, you realize that just because there have been no difference in survival for 40 years that this was still a very big deal. This was still a new standard of care and clearly better than what we had before, but why isn’t it better? The reason why it’s not better is I think that small cell, maybe more than any other cancer, has one of the most, probably the most immunosuppressive microenvironment. And that’s why I do think chemotherapy plays an important role, drugs like etoposide that can really impact the T-reg population by going forward, really targeting that microenvironment, eliminating some of those immune suppressive signals are really what we need to see those immune responses blossom.

Thoughts for the Future: Part 1

DR LOVE: Any thoughts about TIGIT and whether that’s going to be helpful?

DR LIU: Well I’m a believer in TIGIT. As you know, the CITYSCAPE trial, a randomized Phase II, showed that adding tiragolumab, an anti-TIGIT antibody, to atezolizumab, a PD-L1 inhibitor, significantly increased response rate and significantly improved PFS in PD-L1-high non-small cell lung cancer. The PFS hazard ratio of 0.30 in a randomized Phase II trial, that’s pretty striking. We have large Phase III trials that are underway, many that have finished accrual, not just tiragolumab, but other compounds from other companies. I really think TIGIT could be an important checkpoint. Is this going to be something that takes us to the next level? Is this going to replace all of the new frontline studies? Or is it going to be like an IDO which showed early Phase II study benefit that really didn’t pan out in randomized study? I do think it’s going to make a difference. We will see the SKYSCRAPER-02 trial, that’s carbo/etop/atezo, that 133 regimen with tiragolumab or placebo. That large Phase III small cell trial has completed accrual and so hopefully, we’ll get results in the relatively near future.

DR LOVE: Can you talk a little bit more about what actually TIGIT is and how it’s being attacked right now and maybe a little bit more about the trial data you just referenced?

DR LIU: Well TIGIT really is another checkpoint and very similar to other checkpoints in gauge. This one though seems to be co-expressed with PD-L1. What’s interesting in those studies is that looking at TIGIT expression as a predictive biomarker didn’t really pan out, but our models tell us that TIGIT is something that’s co-expressed with PD-L1 and if we block PD-L1 and TIGIT, then hopefully, we’ll be able to generate more antitumor immune mediated responses. The preclinical data really showed that shutting those down, both TIGIT and PD-L1, had a synergistic effect on animal models and in the CITYSCAPE Phase II trial, we did see that benefit.

Now, the problem with the CITYSCAPE study, a randomized Phase II modest size, but not a small study by any means, we see a clear benefit with adding tiragolumab. The response rate, 66% versus 24%. But what the critics would say, and they’re not wrong, is that sort of PD-L1 in the low, the control arm, really did underperform. So while the combination of atezo/tiragolumab gives you that high response rate, that atezo alone didn’t really perform as we really expected it to from the IMpower110 study. And while we see a benefit in PFS with a hazard ratio of 0.30, the control arm also underperformed there. Really wondering if this is real or not. I would say it was a randomized Phase II. Randomization sort of cures a lot of issues in terms of balance and we saw a pretty striking benefit, so I am very excited to see the Phase III data. And the good news is we won’t have to wait too long because most of these studies have already finished accrual and should be reading out hopefully within the next calendar year.

DR LOVE: So coming to your phone soon. Who knows? Maybe another press release. But what about tolerability issues? I see a rash here.

DR LIU: Yeah. So we will see more immune side effects and it’s been sort of my impression that blocking TIGIT does increase immune-related adverse events, but as with many things, I think that goes hand in hand with getting those immune generated responses. And most of those toxicities are Grade 1, so we do see more immune activation and so we see more low-grade immune toxicity. We’re not seeing a lot of high-grade immune toxicity. And so I think it will still be safe, but we need a larger dataset to draw from.

DR LOVE: I saw the infusion reactions there. Have you actually used the drug? What kind of infusion reactions do you see?

DR LIU: So I haven’t seen infusion reactions myself in this. I know that they’re reported and they’re sort of all flavors, but it’s not like an infusion reaction we see with amivantamab, the bispecific that’s sort of a little more regular that we see with most patients. This is still overall a relatively uncommon event.

Case: A woman in her early 70s with Stage IIIB adenocarcinoma of the lung and an EGFR L858R tumor mutation — PD-L1 40% — Matthew Gubens, MD, MS

DR LOVE: All right. Well let’s do one more case. This is from your colleague, Dr Gubens, who brings up what is now becoming a classic question, what do you do with locally advanced unresectable disease that’s EGFR-positive? This is a 72-year-old woman in his practice. Here’s Dr Gubens.

DR GUBENS: We were taking care of a 72-year-old woman. She was a never smoker and she presented with progressive cough and after initial workup, she was found to have a right upper lobe mass, 2.4 cm in size, and there was right hilar and mediastinal disease on initial imaging. A CT-guided biopsy of the primary mass showed lung adenocarcinoma with a PD-L1 of 40%. We did next generation sequencing and this revealed an EGFR-L858R mutation. Because she had multiple station N2 nodes at diagnosis, our Tumor Board recommended definitive chemoradiation which she completed with excellent response. My question to the panel might be, would you consider consolidation durvalumab in this patient with an EGFR activating mutation?

DR LOVE: And, of course, we can expand that out to every other targetable lesion, how you deal with this situation. What are your thoughts? If you saw a patient like that right now, Stephen, what would you be thinking?

DR LIU: Right now, I would not give that patient durvalumab and I’ll tell you, that’s changed over the years. But initially, we do know that patients with EGFR mutations were included in the PACIFIC trial. They seemed to derive a little bit less benefit. And while it’s not part of the label and while durvalumab is, I think, a reasonable option and frankly, probably my board answer at this point. In practice, everything we know about EGFR tells us that they don’t respond to PD-L1 monotherapy. And why would this case be a little different? I think it’s much more likely that we’re not going to see that benefit.

And now that we know that giving a checkpoint inhibitor before targeted therapy makes that targeted therapy much more dangerous, I really worry about compromising the safety of subsequent care. I get the other side point though. If I withhold durvalumab so that in the event of recurrence, I can safely give osimertinib, is that a self-fulfilling prophecy? And by giving durvalumab will I make it less likely that they’ll recur in the first place? And so I see both sides. I don’t think there’s a wrong answer. Earlier, years ago, I was giving durvalumab in that setting. There’s a patient that I do see every couple of months with a CT scan that got durvalumab, has an L858R. Every time I open that scan, you know, I’m holding my breath. Holding my breath every time I open that scan because I’m worried, is it going to be safe to give osi in the event of relapse?

But now that I know that we can use osi after surgery, now that I know the impact in the CNS as well, I do think osimertinib after chemoradiation makes more sense as a consolidation therapy. We do have the LAURA trial. The LAURA trial is a Phase III study that’s ongoing now. It’s not a perfect answer to this though. And so we’ll still be having debates. In the LAURA trial, patients with unresectable Stage III EGFR-mutant lung cancer are randomized to chemoradiation alone with no durvalumab or chemoradiation followed by osimertinib forever, not for 1 year, 2 years, 3 years, but indefinitely. So not really answering the question we’re asking here. A couple different variables there. We won’t have a comparison of osi versus durva. But in my mind, osimertinib makes more sense. How long do we continue that treatment? That I don’t have a great answer for. And indefinite treatment, it’s sort of a big check to write, especially considering chronic toxicity. My hope is that in the future, we’ll be able to use things like ctDNA to really help guide the need for continued therapy.

DR LOVE: It’s interesting, your comment about the board answer because the truth is, there are very few investigators right now who give that answer. Heather is one of them. But a lot of people still say durva. It’s like, you know, sticking with sort of what you have or the data you have. And as you say, it’s another one of these oncology situations. Want to see what happened with this patient?

DR LIU: I do.

DR LOVE: Okay. Here it goes. So let’s see what happened.

DR GUBENS: This patient actually had 2 physician daughters and we discussed at length. This was just as specific data were coming out. Not as much richness to the data we had at that moment. I showed them the forest plot and the EGFR subset. They did decide that they wanted to proceed with durvalumab. This patient went on durvalumab and after 6 months, just routine screening labs, her TSH was elevated at 20, her free T4 was 11. We started her on levothyroxine at 88 mcg with a plan to follow her ongoing. We did decide to continue durvalumab and after 1 more month, again, routine screening labs, she suddenly had high glucose. So her fasting glucose was 317 and an A1C I got that day was 7.3. And ultimately, she was diagnosed with immune-related insulin-dependent diabetes. 24 months out from the end of her abbreviated course of durvalumab, she has not had any evidence of recurrence.

DR LOVE: So I guess a thought too about adjuvant IO, you know, you can see problems. Any thoughts?

DR LIU: Well, you know, there are some evidence, you know, some bodies of evidence, especially more recently, mostly in the metastatic setting, that suggest those that stop therapy due to severe immune-related adverse events have a better outcome even though we’re stopping it. And the general sense is that if you mount enough of immune response to generate those severe toxicities, that you’ll get a good antitumor response. In the adjuvant setting, you know, these are things I think that keep us up at night. Did this person need the durvalumab? Did we sort of change their life in the wrong direction by introducing this toxicity? Or is this what years later is going to prevent her from relapse? And so was this really worth it? We won’t really know. We don’t really know the answer to that. And so I think that one lesson to learn from this is we have to involve the patient in these decisions. They have to know what’s at risk, what’s at stake and really have to be part of that decision making process.

DR LOVE: It’s interesting when the adjuvant melanoma data came out, you know, the BRAF and the IO data came out the same exact, I think it was an ESMO meeting. And so instantly, they had to decide between the 2. And initially, everybody was — because it looked like the benefit was about the same. So initially, people were like — a lot of people were going immunotherapy, you know, it has more of a curative kind of thought. But more recently, you start hearing them say, you know, you can see type 1 diabetes, all this other stuff. BRAF maybe might cause some symptoms, but isn’t going to cause anything permanent. So it’ll be interesting to see how people balance atezo in the adjuvant setting because you can see problems, probably a lot less than with chemo for that matter.

Thoughts for the Future: Part 2

DR LOVE: So a couple other things I want to just get your take on is, we talked a little bit about TIGIT in terms of looking towards the future and a couple other things I wanted to bring up and just get your thoughts on. The first is some data that was just presented at the ESMO meeting. We had seen previously, cemiplimab monotherapy in the EMPOWER-Lung 1 trial. Looked a lot, to me, like the pembro data that got approved as monotherapy. It’s the old palbociclib versus ribociclib. What comes first? I think a lot of people are obviously sticking with pembro. But then, we saw these data just at the recent ESMO meeting in EMPOWER-Lung 3 and this is kind of like the pembro/pem study with pembrolizumab. So using cemiplimab although it looks like they were a little bit more liberal on allowing what kind of chemo, but other than that, it looks a lot like the KEYNOTE study. And it kind of looks like the results are pretty similar too. I was curious what your take was on these data. These are survival benefit. Nice hazard ratio, 0.7. The disease — progression free, 0.56. Again, pretty impressive. So any thoughts about choosing an IO regimen? Now, it looks like there’s another possibility to consider. Any thoughts about these data? Anything to separate it out from the other agents?

DR LIU: Well I think it’s almost an embarrassment of riches. We have yet another option and I promise you there are more right around the corner. I think it’s reinforcing what we know about treating wild type non-small cell lung cancer. That when you add a checkpoint inhibitor to chemotherapy, you improve outcomes, both response, PFS and OS. So I think the cemiplimab data, both mono and combination therapy, are good data. And I think they support its use and I think they sort of merit approval and merit consideration. I don’t see anything in there compelling enough to make me change my practice. So while I think these data are good, I’m not reaching for that first just because I’ve got a lot more experience with some other combinations.

I don’t really see a reason to change that. We’re creatures of habit. There’s a lot of inertia. If I want to change something, then I’ve got to change my EMR pathway. I’ve got to change my authorization pathways. I don’t see a real reason to do that. I will say that one thing about the cemiplimab EMPOWER data is if you’re a guy that likes to make tables so that you can do illegal cross trial comparisons, this study makes it really hard, right? Because the one difference about the EMPOWER-Lung study is they threw everything together. You’ve got squamous, non-squamous, all different types of chemotherapy. Population’s a little different, right? 85% male. A lot more squams than we’d expect. So it’s a little hard to draw big comparisons. We need lots of subsets. And then you start getting into small numbers. So a little difficult to interpret some of the subsets. So I think it’s better just to look at it as a whole package. That when you add cemiplimab to chemo, you improve outcomes. I’m not reaching for it first, but if insurance said, if you want to give pembro — carbo/pem/pembro, you’ve got to call this person and sit on hold for an hour, if you want to give cemiplimab/pem/pem now, carbo/pem/cemiplimab today, you can do that right away, there’s no way I’m doing a prior auth. I’m very comfortable interchanging these.

DR LOVE: So, you know, this is coming up in oncology more and more. Last night, we were talking about genomic assays in breast cancer and people were pointing out there’s 4 or 5 different assays, but there’s only 1 that has data that correlates with treatment benefit and that’s the 1 that people use in general, you know, Oncotype. You think about lung cancer too. We use pembrolizumab all the time, but what do you use with locally advanced? You use durva because that’s where the data is. So it kind of looks like, you know, people — even if you think the agents are the same, bladder, same thing comes up with avelumab. People generally stick with where they have data because I guess that feels safest.

DR LIU: I do. But the way I would interpret this data, while I may not be using cemiplimab/chemo in the frontline setting any time soon, if there was a study 2 years from now that showed me cemiplimab/chemo plus some new anti-TIGIT, anti-LAG-3 — --something was better, by the transitive property, I would assume it’s better than carbo/pem/pembro too.

DR LOVE: Maybe the next race will be TIGIT. So one final question. And we just finished our RCC Meet The Professor series. I think we did like 10 programs. It never got old. Every time we talked about it, every case we heard. There are so many options for first line therapy for RCC. But the big thing that really took that over, and you see this in other parts of oncology, for example, endometrial cancer, is IO/TKI or IO/anti-angiogenic, you know, atezo/bev in HCC. And we have atezo/bev in lung cancer, but we haven’t really seen that concept of TKI/IO play out. I’m curious whether you think that’s ever going to come into lung cancer. Lenvatinib/pembro, which like I said, you know, we talk about that all the time in our endometrial, our Gyn series. Any thoughts about this combination and this strategy?

DR LIU: So I think these strategies we will see. And I want to make it clear that when we talk about TKI/IO, we’re talking about in driver-negative non-small cell lung cancer. Because for ALK, for EGFR, we know it’s not safe to do it there. But if you don’t have a driver, only P53, there’s no actionable driver, can adding these anti-angiogenesis, these multi-kinase inhibitors to checkpoint inhibitors improve outcomes? And I think the answer is going to be yes. We have multiple combinations beyond just lenvatinib. We see cabozantinib. We saw data from sitravatinib and so we have multiple TKIs that are showing pretty comparable improvement in outcomes, but it comes at a cost. And I do think that these combinations are going to be more toxic. And when I’m in the clinic and I’m prescribing pembro, atezo, you know, these are very well-tolerated regimens. And when I’m adding a chronic toxicity there, I really need to see some benefit there. So if I’m going to use that combination, I really want to be sure that that person needs it because the quality of life will be impacted by these chronic toxicities.

DR LOVE: Yeah. We also did a ton of webinars in Gyn oncology and, again, you can talk about pembro/lenvatinib in endometrial cancer all day long because the issues about dosing, dealing with diarrhea, dealing with hypertension. So that’s a good point that, you know, we’re kind of lucky not to have to deal with TKIs in lung cancer yet, but I guess if we see the data and it looks like it’s going to work, maybe post-IO. Any thoughts about that?

DR LIU: Yeah. That is a very heterogeneous population. And, you know, I do a lot of work with drug development. I can say that post-IO, that IO resistant, IO refractory space is very heterogenous, it’s very hard to study drugs in that setting. So if it does overcome resistance, I welcome that. I suspect we’ll see them more in frontline setting where we really are going to need some sort of a predictive biomarker to see who needs that kind of aggressive therapy.