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Jun 12, 2020

Dr. Jason Luke, associate professor and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center, discusses new advances in immunotherapy that were discussed at the #ASCO20 Virtual Scientific Program.

 

TRANSCRIPT

ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Joining me today is Dr. Jason Luke, associate professor and director of the Cancer Immunotherapeutics Center, at the UPMC Hillman Cancer Center.

 

His clinical focus is on immunotherapy for advanced solid tumors, as well as cutaneous malignancies and melanoma. Dr. Luke will discuss key abstracts in the immunotherapy field that were featured at the ASCO20 Virtual Scientific Program, including Abstract 3004, the study of an agent called MGD013, which Dr. Luke presented during the meeting. Dr. Luke, it's great to have you on the podcast today.

 

Dr. Jason Luke: Thank you very much.

 

ASCO Daily News: Do you have any conflicts of interest to disclose that are relevant to the issues we'll discuss in this podcast?

 

Dr. Jason Luke: Thanks. I would like to disclose a few things. I'll note that as a phase I clinical trialist, I try to work with every company in the field. But relevant to the abstracts, I have been a consultant to most of the big pharmas that have advanced these. So specifically, EMD Serono, Genentech, EMS, Merck, and some others.

 

ASCO Daily News: Dr. Luke, are there any advancements in the immunotherapy field that will likely support new standards of care?

 

Dr. Jason Luke: So thank you. Yes. In fact, this was a big year for immunotherapy. I think ranging from abstracts with a high immediate impact on the standard of care all the way to -- or earlier truly -- research studies that I think we'll look back on and realize this was the year when that technology started to mature.

 

So when thinking about abstracts-- presentations that are going to have an immediate impact on the standard of care, there are really two that I would highlight. One of them was called the JAVELIN Bladder 100 trial (Abstract LBA1). And the second one was a clinical trial called KEYNOTE 177 (Abstract LBA4). So I'll talk about them individually at first. And I think they introduce ideas about using immunotherapy you should be cognizant of to inform your practice.

 

So for the first one, the JAVELIN Bladder 100 trial, is a clinical trial in advanced urothelial cancer, in which patients were treated in the frontline setting, albeit for that first treatment and the standard of care setting, with cisplatin-based chemotherapy. And as they completed their cisplatin-based chemotherapy, they were randomized to either get the anti-PD-L1 antibody, avelumab in a maintenance sort of approach, or waiting until they had progression and going on to standard therapy with second line chemotherapy, as would be commonly done.

 

So the clinical trial showed an overall survival advantage to the maintenance approach of giving avelumab or anti-PD-L1 in that setting. And this is a pretty big deal because this is really the first maintenance approach that really has been associated with an overall survival advantage in solid tumors in general, but specifically a bladder cancer.

 

Now obviously the context for such an approval is the activity of PD-1 or PD-L1 blocking agents in urothelial cancer. And probably everyone who is listening is aware that multiple checkpoint inhibitors are approved for second line usage in bladder cancer. And all of you listening are probably also aware that there's been a lot of discussion in the field of urothelial cancer about moving checkpoint inhibitors into the frontline setting.

 

And the FDA had to release a guidance that that should not be done without the obvious presence of PD-L1 positivity. So a very interesting thing from the JAVELIN Bladder Trial was that the benefit to maintenance avelumab appeared to be independent of PD-L1 status. So in other words, everyone, or the total population of patients, benefited from getting that chemotherapy and then going on to get avelumab, whether PD-L1 positive or negative.

 

So I think that's a big deal. So based on these data my read of it and the conversations that I've had with other experts in the field of GU malignancies aren't to suggest that this is a new standard of care, that patients should after completing initial chemotherapy go on to get a PD-1 or PD-L1 agent.

 

Now that being said, it isn't without some controversy. These maintenance approaches have been criticized over time about cherry picking patients and discontinuing chemotherapy that might otherwise be active. One can't really know here how many patients would have done well without the avelumab for a long time.

 

It's also obviously the case that patients could go on to get second line PD-1 or PD-L1 agents on label. So again pembro, nivo, atezo, durva, avelumab, these are all approved for second line therapy. And in this clinical trial, because it was done ex-US, only about 40% of the patients who were on the placebo-matched arm actually went on to second line PD-1.

 

So this trial definitely did not test the question of maintenance PD-1, PD-L1 versus giving it in the second line after an initial progression event in the front line. And that is obviously a criticism of these data. Now that being said, all of you who have treated patients with urothelial cancer realize what an aggressive malignancy this can be and how these patients can sometimes be rather frail.

 

And what we can run into is that at the time of progression after frontline chemotherapy performance statuses just dwindle very rapidly, such that you can't really, fully give them a shot to get the second line PD-1 immunotherapy. So here, though, by giving the therapy immediately after the initial chemotherapy without waiting for progression, we make sure that all patients get access to that therapy.

 

So despite the controversy around subsequent lines of therapy, et cetera, I think most people who view this data really do find it to be practice changing. And moving forward we really should be considering immediate initiation of anti PD-L1, or PD-1 I suppose, after chemotherapy. So that was the first abstract to highlight in that space, the JAVELIN Bladder 100 study.

 

The second study was the KEYNOTE 177 study (Abstract LBA4). This was a randomized phase III trial in the frontline setting for MSI-- or MicroSatellite Instable-- colorectal cancer for the use of immunotherapy with pembrolizumab, as opposed to chemotherapy. And so again oncologists listening will be very well aware that MSI status has become an important biomarker in our field, selecting out patients, especially with colorectal cancer but actually any cancer type, who if they have MSI status can be treated in this integrative care setting with the anti-PD-1 or pembrolizumab.

 

One of the questions that has been looming and seemed like had an obvious answer, and, in fact, this trial supports, was whether that biomarker would be strong enough to move that immunotherapy into a prechemotherapy setting. So to date the use of the MSI biomarker has been to select patients after they failed standard therapies to go on to get immunotherapy.

 

So in colorectal cancer, patients would get FOLFOX/FOLFIRI as per standard. And if they were MSI, they would be treated thereafter with pembrolizumab. So in this study, they moved that biomarker selection into the frontline, looking at MSI high patients and randomizing them to either get pembrolizumab or standard chemotherapy.

 

And the answer here, as was expected, was that patients who are MSI high in their tumor who got immunotherapy in the frontline, in fact, did better than those patients who got chemotherapy in the frontline. And so I think that's an important clinical practice changing algorithm. So we should be testing all our patients upfront for MSI with colorectal cancer, and one might even argue actually other tumor types, because we find that the patients who have that phenotype, their rates of response approach 50%.

 

And those responses tend to be very durable with the median not being reached in these kinds of trials. So that quality of immunotherapy response, I personally think that's the thing that we all really like about immunotherapy, is that for the small patients where they get that benefit from immunotherapy, it can sometimes be long lasting-- and even life lasting-- kind of benefit. I think these data are very important, again, to move this biomarker selection of patients for colorectal cancer by MSI high status into the front line and give them immunotherapy if we find that.

 

These data don't come as much of a surprise given that we know in the adjuvant setting, in fact, the MSI high patients do worse with chemotherapy in the stage two setting. So again, these data don't come as a big surprise. But they do support a change in practice to move immunotherapy into that frontline setting.

 

And I would say as a sort of forward-looking discussion point, given the broad approval across cancer types for MSI high tumors to get pembrolizumab, one wonders whether or not this phenomenon will begin to come forward and other tumor types where we know MSI could be present, such as gynecological cancers and some others. We'll watch the field. But I think that that's something to be excited about for immunotherapy coming forward and potentially displacing chemotherapy in the front line for different cancer types.

 

ASCO Daily News: Dr. Luke, what are the other studies that really stood out for you this year?

 

Dr. Jason Luke: There were three other big trials I think that generated a lot of buzz that I think I should be highlighted. They don't quite change standard of care at this time. But they do influence standard of care.

 

And so there are three of them. One of them was the CHECKMATE-9LA study of lung cancer (Abstract 9501). There was a second phase 2 study called the CITYSCAPE study (Abstract 9503), also in lung cancer. And a third study in bladder cancer called the IMvigor010 (Abstract 5000) or 10 study.

 

So just to discuss them-- so CHECKMATE-9LA in fact did lead to an FDA approval of the combination of nivolumab and ipilibumab or PD-1 CTLA-4 in combination with chemotherapy for the frontline management of non small cell lung cancer. So this regimen is somewhat different than the chemo I-O combo that people will be cognizant of right now. So the standard of care now, there's an approval for chemotherapy with platinum-based chemotherapy and a second agent, such as pemetrexed, with pembrolizumab in the front line.

 

This trial took a different tact. And they randomized patients to either get regular chemotherapy, platinum-based chemotherapy, or they would get the combination of ipi and nivo with two cycles only of platinum-based chemo. So you could refer to this as some sort of platinum sparing approach. And the rationale for this was that perhaps because patients with lung cancer can have a very aggressive course, having that immunotherapy onboard up front might allow a space for immunotherapy then to kick in and have a longer term benefit.

 

So this trial is a positive Phase III clinical trial. And actually just before the ASCO virtual meeting, the FDA approved this regimen for the use in patients with lung cancer. Now you might be listening and thinking, well, wait a minute. You just told me about their new standards of care. And you're telling me this is approved. So what's the deal?

 

And so what the deal is is that it's not completely clear at this time that this sort of an approach would be better than using the chemo pembro combination that's already approved. And the toxicity profile using doublet checkpoint blockade with PD-1 and CTLA-4 is not insignificant. Sorry for the double negative there. But in other words, you're generating a lot of immune-related side effects for patients by giving them ipi/nivo and chemotherapy.

 

So the question then becomes, so which patients then should you give chemo pembro to versus giving chemo ipi/nivo to? And unfortunately at this time, we don't really know the answer to that question. So that then sets us up with a tough spot to sit in, that we don't really know how to use these regimens either way. And we know one of them causes more side effects.

 

So what I would say right now is that it's not clear that this advances the field in terms of changing the standard of care. But I'll be very interested to see the long-term outlays in terms of overall survival in this clinical trial. So the trial we would want to see would be chemo pembro versus chemo plus ipi/nivo.

 

But these trials were done chronologically at similar times. And the standard of care had not switched to chemo pembro yet when they had started this trial. So certainly that's a future trial we would look forward to. I think it is possible that the chemo ipi/nivo trial might have the potential to have better overall survival over a long period of time, relative to chemo pembro.

 

And the reason I say that is we can see that in melanoma where giving ipi and nivo does appear to give better longer overall survival, but you don't see that effect until about two to three years after you start ipi/nivo relative to starting nivo monotherapy. So we're not really going to know whether or not the long term survival of this quadruplet regimen of platinum doublet plus ipi/nivo is actually better than the triplet of platinum doublet plus pembro.

 

We're not really going to know that in a head-to-head trial for a long time. And even just comparing two trials head-to-head, we're not really going to know that again for at least a couple of years. So I don't know whether or not that trial really changes practice yet. But it'll be very interesting to watch it over time.

 

The second trial I wanted to talk about that really stood out was the CITYSCAPE trial (Abstract 9503). And so this is a nice name for a clinical trial. Essentially what it is is looking at a combination immunotherapy in the PD-L1 high subset of non small cell lung cancer. So in patients with greater than 50% TPS In lung cancer, the molecule, the PD-L1 antibody atezolizumab, was combined with an anti-tigit antibody in that population and randomized against atezolizumab plus a placebo.

 

And the idea here would be to look for a second combination checkpoint that's not CTLA-4 and see if that could have more activity relative to a PD-1 PD-L1 monotherapy in that PD-L1 high population. So again, all of you are aware that PD-1 monotherapy is approved in that setting. PD-1 and PD-L1 are both approved for PD-L1 high patients in frontline lung cancer.

 

And what they observed in this CITYSCAPE study was an improvement in the response rate for the combination immunotherapy relative to the PD-L1 plus placebo. And that was statistically significant. And it was of substantial interest.

 

So I think that's very interesting. And based on those data, in fact, the company advancing this tigit antibody that makes atezolizumab has rushed forward into a series of randomized Phase III clinical trials, where they're combining atezolizumab with this tigit antibody across a number of diseases. The first two trials will be a non small cell lung cancer as well as small cell lung cancer with the idea that this new PD-L1 plus tigit regiment essentially is going to replace a PD-1 or PD-L1 monotherapy either as-- oh, sorry, either as monotherapy or in combination with chemotherapy and various different indications.

 

So this is really interesting because the toxicity profile of this combination regimen was quite modest and in fact look mostly like a PD-1 PD-L1 monotherapy. So this wouldn't be the addition of a second checkpoint that actually doesn't increase the toxicity, but might amplify the benefit. And so why would that be the case?

 

Well the checkpoint tigit we know from basic biology is also associated with the T cell activation state in the tumor microenvironment. And it may very well be that this is yet another checkpoint that's important in the tumor, that by blocking it we might not increase the overall toxicity because where the tumor is where the action is at. And it might increase the benefit.

 

And that would be different than CTLA-4 or ipi, where the effect is broadly throughout the whole body and not localized in the tumor microenvironment. So that's a very interesting molecule, this tigit molecule to keep your eyes on, because I think there will be a number of Phase III trials coming forward the next few years It'll be very interesting to see if we can find other combination immunotherapies.

 

The third abstract that I wanted to dwell on quickly that stood out-- again, doesn't change practice, but it's important to be cognizant-- was IMvigor 10 or 010 (Abstract 5000). And this was a bladder cancer randomized Phase III adjuvant clinical trial. And the idea was high risk patients with bladder cancer are randomized to either get atezolizumab or to get placebo in the adjuvant setting.

 

And really as, I have to say, a shock to most of the people in the field, there was no difference in rates of relapse or overall survival in high risk urothelial cancer for patients who got adjuvant PD-L1 relative to those who got placebo. And this is one of those things where don't count your checks before they're cashed, or don't count your eggs before they're cracked, or whatever the euphemism goes. Everyone assumed this would be a positive clinical trial.

 

In melanoma when we moved PD-1 antibodies from the metastatic setting into the stage three setting, it was a slam dunk. It was fabulous, unbelievable-- hazard ratio of 0.5. Yet here we see in another disease, which is responsive to immunotherapy in the refractory disease setting, we see no difference in the adjuvant setting. So I think that's really an eye opener and, again, just suggests why we have to do these trials.

 

My dad used to like to say, that's why they play the games. Let's talk about sporting events with atypical outcomes, things you didn't expect. So that's again what we saw here. So adjuvant PD-1 or PD-L1 is not a standard in bladder cancer. There are some other clinical trials that are ongoing to look at other PD-1 agents that have slightly different designs. And we'll be very interested to see what the results of those kinds of clinical trials look like over time.

 

ASCO Daily News: Are there any other clinical trials that our listeners should be aware of?

 

Dr. Jason Luke: Yes, so there are also a whole handful of trials that I think are worth quickly pointing out because I think they give us indications around better using agents that we already have. So in melanoma there were a couple of abstracts presented that looked at the use of CTLA-4 with a PD-1 in second-line melanoma. So in patients who got a frontline PD-1 an open question is, should you give them ipi as the second line, so PD-1 followed by CTLA-4? Or what about the idea of continuing the PD-1 and adding the CTLA-4 antibody on top of it?

 

And so there were two abstracts. There was a prospective open label Phase II study, in fact, that I designed. It was our study (Abstract 10004). And what that showed was that where we would expect a response rate of about 13% to ipilimumab in the second line as a monotherapy, in our Phase II study of 70 patients, we got a 27% response rate. And that trial was augmented by another abstract from the Melanoma Institute of Australia, who aggregated their experience of what they had done in their standard practice in the second line.

 

And in the patients who had gotten ipilimumab plus nivolumab after a PD-1 (Abstract 10003), they observed a 32% response rate. So if you put these two studies together, you're now up about 250 patients between both series. And you get a response rate between both of them around 30%. And that looks to be about a doubling of what we would expect in standard care setting of just getting ipi monotherapy after PD-1.

 

So I think that's a really interesting thing to be aware of. In my practice I tend to give that combination regimen after initial PD-1. And I think we'll look forward to a study from SWOG, which is actually randomized patients to get ipi/nivo versus just ipi after a frontline PD-1. So I think that's a really important abstract to be aware of.

 

The other study that I'll be-- but I'll just share, however, was that in contrast to that, there was a series of studies presented in renal cell carcinoma, where this paradigm did not appear to be true. So there was an abstract called the FRACTION study in renal cell carcinoma (Abstract 5007), as well as the Hoosier Oncology Group GU16-260 (Abstract 5006). In both of those studies, there did not appear to be a big benefit to adding ipi after a patient had progressed on PD-1.

 

And that was interesting because in the FRACTION study (Abstract 5007), they used ipi/nivo. And they got responses in the second line. But in the Hoosier study, it was less clear. And so I think the renal guys feel like if you're going to use ipi/nivo, you need to do it right away upfront. And you shouldn't do the sequential approach of giving a PD-1 and then adding on ipi later.

 

And it's interesting to contrast those two things because that's a difference between tumor types, where we think there might be more benefit to giving that combination or waiting for the combination of melanoma, whereas in renal, if you're going to use it, you should really come in guns blazing both checkpoints at the same time.

 

One other study I want to do just highlight quickly was also in melanoma, where the group from Sloan Kettering did a study looking at two doses of ipi/nivo versus four doses of ipi/nivo. And not to dwell on it too long, but what they observed was essentially all of the benefit and all of the toxicity appeared to be associated with just the first two doses of ipi/nivo.

 

In other words, when they looked at an early CT scan to look for responders, all the responding patients had already basically had their benefit after the first two doses. And none of the patients who hadn't already benefited by two doses actually went on to benefit at four. So this was a pretty small study. It was upwards about 25 or 30 patients. But I think this really deserves further follow up.

 

And I think it emphasizes, however, that in clinical practice, there is no need to really push the envelope in giving more ipi/nivo, especially if patients have toxicity. So if patients get a couple of doses and they get toxicity, you do not need to go back to pushing them to get more doses. We'll be very excited to look for future data to really look into this so we can really optimize the use of combination immunotherapy in the broader population.

 

ASCO Daily News: Dr. Luke, are there new treatment approaches or agents in development that you are particularly excited about this year?

 

Dr. Jason Luke: Yes, so there were, as I mentioned, a couple of abstracts around adoptive cell therapies in solid tumors that I think we're going to look back on this year's ASCO and say, wow, this is the year when these things really started coming to the forefront. And there were three of them that I'll highlight quickly.

 

One of them is a drug called lifileucel. In fact, that is a tumor-infiltrating lymphocyte product. And in melanoma, an updated data series was presented on a group of about 70 patients who had undergone tumor excision and then harvesting of TIL. And then a TIL product was made. Patients were given lymphodepleting chemotherapy and were reinfused their TIL . (Abstract 10006)

 

And what was exciting about it was the stability of these results over time. So in these patients, a response rate in 70 patients was observed at 36%. And realize that these are patients who already had PD-1. They had CTLA-4. They had BRAF. These were refractory patients. So a 36% response rate-- quite impressive.

 

The other thing that was very interesting to be observe was that the duration of those responses in the refractory disease setting was not reached. So in other words, the patients who responded did very well. And then the final thing on that one to be aware of was it looked like patients who would benefit from that therapy were disproportionately those who had not benefited from previous PD-1 therapy.

 

And certainly, that's a big unmet need in melanoma. And in the melanoma field, we're fairly confident that this therapy is going to be approved by the FDA either later this year or next year. So being cognizant of cell therapy for solid tumors, at least in terms of TIL for melanoma, is going to be important.

 

The other two abstracts I'm going to put together quickly. One of them was about SPEAR MAGE-A4 TCR transduced T cells (Abstract 102), as well as a second abstract about HPV E6/E7 TCR transduced T cells (Abstract 101). So what are TCR transduced T cells, you might ask?

 

What this is, is taking a patient's own lymphocytes and then ex vivo transducing them with a lentiviral vector most commonly to express a T cell receptor that's been identified from a different patient. So that T cell receptor can be specific for a certain antigen. So you'll have heard-- I mentioned MAGE-A4-- as well as HPV E6/E7.

 

So these are antigens that we know can be expressed to certain degrees in certain tumor types. For example, MAGE-A4 is highly expressed in sarcomas as well as some esophageal cancers. And HPV is obviously highly expressed in HPV-associated cancers, such as cervical cancer and others-- head and neck, et cetera. And so these studies were very interesting because obviously this is a somewhat complicated process, sort of like the TILs I told you about before, but it adds an extra layer of genetically modifying the product.

 

But, again, they saw high levels of response in tumor types that had these antigens. And those responses tended to be durable over time. So there are randomized trials coming forward now to look at these agents. And I'm very excited that over the next couple of years, we're really going to see a movement of cell therapies to the prime time and maybe even in the standard of care setting for patients with multiple solid tumors.

 

ASCO Daily News: Absolutely. Can you tell us about new agents that will likely move the field forward or have already done so?

 

Dr. Jason Luke: Yes, so there were a handful of abstracts here. But I think there are two conceptual things that I'm going to highlight. It isn't so much the individual agents, I would say, but rather the concepts around them. I'll give you the names of the agents so you can look them up.

 

But one of them was an agent called MGD013 (Abstract 3004). But the reason it's of interest is that it's a bispecific antibody. So disclosure, I was the presenter of this abstract. But I think it's very interesting because what it gets at is a future of using antibody engineering technology to bring forward novel agents. So MGD013 is a bispecific PD-1 and LAG-3 inhibitor.

 

So those are two immune checkpoints that are being investigated separately with monoclonal antibodies. But here we have one drug that can hit both of those. And so what was interesting was the drug was safe. And the response was seen across a host of different diseases.

 

But perhaps most interestingly in the trial, we combined MGD013 with the HER-2 antibody margetuximab. And margetuximab is an FC-modified and optimized HER-2 antibody. And in patients who had refractory HER-2-positive tumors that were PD-L1 and LAG-3 low, the combination of MGD013 with margetuximab generated more than 40% treatment responses.

 

So this really fits the paradigm of what we were hoping to do. And you may have heard of this-- "turning cold tumors hot" is how we sometimes talk about this. In other words, we can identify a biomarker, target that with the margetuximab in HER-2, and then come in with immunotherapy. And because the first therapy was successful, it makes the second therapy likely to be successful as well.

 

So I would be aware of these bispecific approaches. Some of them have come forward from leukemias already. And I think in solid tumors, it will be interesting as well.

 

And the final one I'll note were the combinations of VEGF or VEGFR inhibitors with PD-1s or PD-L1s. And in fact there were so many of these combinations presented that I don't really have time to go over all of them. The listenership will be cognizant that the standard of care has changed in kidney cancer and recently in hepatocellular carcinoma in the front line to include these kinds of combinations.

 

But there were data presented for endometrial cancer (Abstract 6083), mucosal melanoma (Abstract 10040), colorectal (Abstract 4019), bladder (Abstract 5013), prostate (Abstract 5564), lung (Abstract 9610), more, that these combinations look to be quite active in the PD-1 progressed setting. And in fact clinical trials are now starting to move these combinations into earlier lines of therapy as well. So I think this combination of VEGF blockade with PD-1 is really going to be something to be on the lookout for because I think this is going to expand the horizon of immunotherapy within and across multiple solid tumors.

 

ASCO Daily News: Excellent. Thank you, Dr. Luke. So I'd like to let our listeners know that the abstract numbers relating to all of the studies Dr. Luke discussed today are on the transcript, which is published with this episode. Dr. Luke, thanks again for your insights on these incredible developments in the immunotherapy field.

 

Dr. Jason Luke: Thank you very much for having me, Geraldine.

 

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The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.