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Director of the Lung Cancer Medical Oncology Program at Cleveland Clinic Taussig Cancer Institute, Nathan A. Pennell, MD, PhD joins the Cancer Advances podcast to discuss the KRYSTAL-1 trial, a new treatment option for patients with advanced non-small-cell lung cancer with KRASG12C mutation. Listen as Dr. Pennell explains the trial and findings that were presented at the American Society of Clinical Oncology (ASCO) 2022 annual meeting.

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KRYSTAL-1 Lung Cancer Trial

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances at Cleveland Clinic Podcast for Medical Professionals, exploring the latest innovative research in clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase one in sarcoma programs. Today, I'm happy to be joined by Dr. Nate Pennell, director of the lung cancer medical oncology program here at Cleveland Clinic Taussig Cancer Institute, and a co-investigator of the KRYSTAL-1. He's here today to talk to us about this clinical trial. So welcome Nate.

Nathan Pennell, MD, PhD: Thanks Dale. Really glad to be able to join you.

Dale Shepard, MD, PhD: Sure. So just start out, tell us a little bit about your role here at Cleveland Clinic.

Nathan Pennell, MD, PhD: Well, I've been at the Cleveland Clinic now for over 14 years, remarkably enough. So I run the lung cancer medical oncology program and clinical trials program. And then more recently I'm also the vice chair of clinical research for the Taussig Cancer Institute.

Dale Shepard, MD, PhD: Excellent. Well, today we're going to talk about lung cancer, of course, and lung cancer research, and specifically this KRYSTAL-1. So to start out, can we just start in a very general way and talk about patients with lung cancer? What are the categories of treatment available? We're going to talk about one specific type, but maybe as an overview, like how do we treat lung cancer?

Nathan Pennell, MD, PhD: Yeah, no, it's fascinating. So when I started off in the mid two thousands, non-small cell lung cancer, which is the most common type of lung cancer, was really considered one disease. And everyone got chemotherapy and everyone generally did poorly and did not live very long. And starting in about the mid two thousands, they started recognizing the importance of at least differentiating out the different subtypes of non-small cell lung cancer. So we know that about two thirds of them are what we call adenocarcinoma of the lung. And about a third is squamous cell carcinoma of the lung. And then there's some poorly differentiated ones that don't fall into either of those two groups. But even within that group, we know that in the adenocarcinoma group, that there is many different subtypes now. So this all started with identification of something called the epidermal growth factor receptor mutations present in about 15% of lung adenocarcinoma. And they have a different prognosis, more common in non-smokers.

And since then there've been multiple generations of targeted drugs that have specifically targeted that. But that's really changed our understanding that lung cancer is not a single disease. And now really it is a field that has exploded with development of so-called targeted drugs, targeting specific genetic biomarkers that we now routinely test for in everyone with lung cancer. So it's gone from being a very simple disease, treated with a single treatment, to now a very complex disease treated with probably a dozen different treatments.

Dale Shepard, MD, PhD: So it's a very large group of tumors that are really a collection of rare tumors.

Nathan Pennell, MD, PhD: That's exactly right. And I have to point that out whenever someone asks me why we're not accruing to clinical trials, that in fact, I'm not trying to put a hundred people with the same disease on a clinical trial. I have to put two people on a dozen different trials because they really are a collection of rare diseases. Although the one we're going to talk about today is not that rare, which is actually pretty exciting.

Dale Shepard, MD, PhD: So I guess it really comes down to right treatment for the right patient and sort of identifying the characteristics of those patients. How has that turned into improvements in responses and survival and things? What are some of the big wins there?

Nathan Pennell, MD, PhD: Well, just to put it in perspective, so if we look at the last big phase three chemotherapy alone trial for all non-small cell lung cancer, which was published in 2002, and it basically was four different combinations of what we call platinum double chemotherapy compared to one another. And all of them did exactly the same and the median survival on that trial was about nine months. So when I started treating people with lung cancer, I used to say approximately half of my patients lived for about the first year, and then the other half passed away in the second year. And so it was really tough actually to get people to go into the field. But from a science standpoint, it was changing quite a bit.

So just to jump forward to 2022 for certain subsets, so let's say for example, something called anaplastic lymphoma kinase, or ALK positive lung cancer, which is probably about one in 50 people with adenocarcinoma of the lung have this gene fusion. If we test for and identify these people up front and treat them with a, we're now up to our third generation of targeted treatments, which is a pill that they take once or twice a day, the median survival has not yet reached at five years. So we're talking about people now living 5, 6, 7 years. I'm actually coming up on the 11th cancerversary of an out positive patient, one of the first ones to go on a targeted treatment for this drug.

Dale Shepard, MD, PhD: Wow, impressive. We're going to focus now on this crystal trial. So tell me a little bit about the target that was being tested. And as you mentioned, not such a rare target. So tell us a little bit about that.

Nathan Pennell, MD, PhD: Yeah. So we're going to talk about the KRAS mutations. So KRAS mutations are sort of the newest target, but they're actually the oldest target because KRAS was pretty much the first oncogene identified in cancer. And we've known forever that it's been present at an extremely high rate in lung adenocarcinoma, smaller percentage of squamous cell carcinomas, but it's probably 25 to 30% of lung cancer. And up to this point, it's only real relevance has been if you identify it, you know that they don't have anything else that you can actually target. Probably had a worse prognosis than other types of lung cancer. And of course, KRAS mutations, there's lots of different KRAS mutations. In lung cancer, though there's a particular one called G 12 C, which is present in almost half of lung cancer, KRAS mutations. So it represents overall probably about 14% of lung adenocarcinoma patients.

So it's as common as EGFR mutations, but what makes this also interesting is that it is more common in people who have smoked previously. Up to this point, most of our exciting targeted treatments in these, what we call driver ONCA genes like EGFR and ALK have been mostly enriched in people with not much of a smoking history or even non-smokers. Whereas now we have a large subgroup of people who may have been former smokers and have treatments for that. So it's a common type of mutation, a common patient we see in a major unmet need, because up to this point, the only treatment really has been chemotherapy, and more recently immunotherapy.

Dale Shepard, MD, PhD: So this trial specifically, what were you looking at?

Nathan Pennell, MD, PhD: Yeah, so the KRYSTAL-1 study, so it's a phase one study, although it's much more like modern phase one studies than older phase one studies. So there was a dose escalation of a drug called Adagrasib. So Adagrasib is an irreversible small molecule inhibitor of the KRAS G 12 C, which keeps it in its inactive GDP bound state. So KRAS has previously been considered a so-called undruggable target, but they found in its inactive state, they can actually bind and inhibit it. And it showed activity in its very initial dose escalation. So more than 50% of the first dozen or so people on the phase one trial responded, which was incredibly exciting. And so they then expanded this into essentially a phase two portion of the trial with 116 patients. And the presentation at this year's annual ASCO meeting, we announced the final results of the so-called registrational cohort that the FDA is considering.

So these were previously treated non-small cell lung cancer patients. They had to have had chemotherapy and prior immunotherapy, which is the standard of care for first line. They could have brain metastases, although they had to be stable and treated. And they then would go on Adagrasib, and the primary endpoint was response rate. The results basically showed a response rate of 43%, which was pretty exciting. Only about 20% of people did not have at least stable disease, so pretty good disease controlled rate, with a duration of response of eight and a half months and a progression free survival of six and a half months. So this is clearly an active drug, and I believe this cohort is being evaluated with breakthrough status at the FDA and hopefully will become approved based these results.

Dale Shepard, MD, PhD: And the duration of response you just listed is better than what survival was or equivalent to survival when you started all of this.

Nathan Pennell, MD, PhD: Yeah, it's interesting. So the survival in the cohort was just over a year, 12.6 months. But considering they'd already gone through all of the available standard treatments, I think that's pretty impressive. This is an area where there's still a major unmet need. People who've already had their best available chemotherapy or immunotherapy and then progress, really the standard at that point is single agent chemotherapy like docetaxel, which has a response rate of less than 10% and a progression free survival of about three to four months. It's really unimpressive. So this definitely, I think, represents a major advance, and probably will at least the class of KRAS G 12 C inhibitors. So this is not the first approved drug in 2021. Sotorasib, which is also a G 12 C inhibitor was approved by the FDA. But this class of these drugs will clearly become the new standard of care for this population after prior treatment.

Dale Shepard, MD, PhD: So I guess with your involvement, not only treating patients from a very practical standpoint, but your research sort of background as well. What are your thoughts about unmet need? Let's talk about that just briefly. There is a drug out there. Is this drug clearly better? Do we need two drugs? How's this going to shake out as we have two drugs, three drugs, four drugs? What do you see in terms of like sequencing or how do we work with multiple drugs for the same thing in a disease?

Nathan Pennell, MD, PhD: Yeah, no, that's a complicated question. I think, well, there's two different situations where this is important to think about. So right now, we're sort of in the phase where all of the drugs in early development, were all undergoing trials at the same time. And one of them reports out and gets approved, but the others are also kind of close to approval. And so I think you can still say that all of the ones approved within the same kind of 12 month period, still meet that original unmet need. And it's very interesting, so we traditionally think that to get approval for a drug by the FDA, you have to beat the established standard approved drug in a phase three study, but that's not true with targeted drugs that are highly effective. So we've seen in the lung cancer field, many drugs now approved based upon relatively small single arm cohorts with high response rates.

And I think that is one, the FDA understands how poor the comparator is. And two, you know it when you see it that it's a real active drug. So if you've got something that has a close to 50% or higher response rate with a progression free survival, as you said, that exceeds the median survival with previous treated trials, then these tend to get at least accelerated approval. Although oftentimes they do have to then prove that in a phase three trial after the fact. So I think that these still meet, both Sotorasib and now Adagrasib clearly meet, in my opinion, the bar for accelerated approval. Now, is it better than Sotorasib? So the response rate to Sotorasib was in the high thirties. This is 43%. I would say that's not a significant difference between the two. The progression- survival in both of them was fairly close, sort of in that eight to 10 month range.

The one thing that might distinguish Adagrasib though, is it does seem to have good activity in the brain. So we know in on the trial, 20% of people had brain metastases, and then they published a separate cohort that was presented in a clinical science symposium at ASCO, looking at a separate cohort of those with untreated brain metastases. And in both those groups, the response rate seemed to be in the 35% range, which was very close to the overall systemic response rate, suggesting that there's good CNS penetration with this drug. And so that in the patients with brain metastases may differentiate this as a better drug than Sotorasib. Of course, until we learn more about the activity of Sotorasib in the brain. So I don't want to say that it's definitely better. We just don't have the data on that subset of patients from the older drug.

Dale Shepard, MD, PhD: That's a good point. Those are, I guess, the way you differentiate, establish the one works in a refractory or recurrent setting or a different stage of disease, rather.

Nathan Pennell, MD, PhD: Right. And, and so one of the things you mentioned is about, do we need now a third, fourth, fifth drug? And I'll tell you that there's probably a dozen or more of these in development from different companies. And I would say we don't because this is super exciting, this is a probably in my opinion, going to be the defining area for targeted treatment in lung cancer over the next decade, is targeting KRAS and not just G 12 C, but there's G 12 D inhibitors, there's pan KRAS inhibitors coming. It's going to be incredibly exciting. But the response rate that we're seeing here, the progression-free survival that we're seeing here, is not on the same level of what we're expecting with highly effective targeted treatments in our other lung cancer subgroups. So if I were to give someone with an EGFR mutation, the best available tyrosine kinase inhibitor, we would expect closer to an 80% response rate with progression free survivals in the 18 to 24 month range.

So that's sort of the bar that we want to meet. And these drugs really, I think, represent the first step into this field. And we now need to figure out how to make it better, how to make it last longer, how to make it work for more people. We need to try it in different lines. So does it work first line better than it did in second line? Almost all targeted drugs do when it's tested in that setting. We know that patients with KRAS mutant lung cancer tend to do very well with immune therapy. So there's lots of combination trials between immune therapy and these drugs. One of which we're hoping could open here at the Cleveland Clinic. And then of course, combinations with other map kinase pathway inhibitors. I think lots of things to explore. And so I would not be super enthusiastic about being the fifth or sixth single agent G 12 C inhibitor in this field, because I think before long, it's going to have moved on to some other combination.

Dale Shepard, MD, PhD: I'm just going to take a really quick pause and point out that as a sarcoma guy, I'm ridiculously jealous of your response rates.

Nathan Pennell, MD, PhD: I know. We look at 43% and we're like, eh, but it's not 70%. And you're like, but I realize that that still looks pretty good for a lot of fields that still haven't quite made it there. It is kind of an embarrassment of riches, a little bit with the targets in lung cancer. But nonetheless, almost all of our patients are still going on to eventually progress and die still, so a lot of room for improvement,

Dale Shepard, MD, PhD: Which do you think is going to be more promising? Combinations with chemo, with targeted agents, with immunotherapy. Any way to predict that?

Nathan Pennell, MD, PhD: It's a good question. I would say in the combination with immunotherapy, that has not panned out with other targeted therapies in lung cancer. Although most of those targeted therapies have been specifically in populations that don't seem to respond well to immunotherapy. And so immunotherapy may not really be all that great a partner. But part of the other problem is that there have been issues with toxicities, unexpected toxicities when combining targeted treatments with immunotherapy. There have been some data released suggesting that G 12 C inhibitors may be able to be safely combined with immunotherapy. So I think that is potentially promising. Usually targeted treatments also seem to work a little bit better when combined with chemotherapy, although it's not a huge jump, you would say maybe prolonging progression free survival by a certain amount. So I am more optimistic about perhaps targeted combinations along the map kinase pathway or things like ship two inhibitors, which are also involved in signaling along map kinase that may be active across lots of different mutations within that pathway and not just the KRASS G 12 C.

Dale Shepard, MD, PhD: So I guess I'm going to ask a somewhat practical question. You get a drug, a specific target, great responses, it's effective, it's good treatment option for a patient. But only if you get it to the patient. And so historically, some of these targeted drugs, very specific things, it's been a challenge. Having people get tested, having people actually have access it. Is it safe to say that the drug that's currently available, is it really getting the uptake one might think based on docs identifying the target and actually putting people on trial? And is that a problem with this class of drug?

Nathan Pennell, MD, PhD: That is an area that, vastly underappreciated, is the practical implementation and how do we get all of our exciting treatments that show such great efficacy to all of the people that benefit from them? I think in the KRAS space, patients luckily will benefit from their predecessors in the targeted world in lung cancer. So we already have seven approved targeted drugs for different classes of molecular derangements in lung cancer. And so broad testing for these molecular mutations, gene fusions, et cetera, is already established and understood. Although I will say that it's probably still not as good as it needs to be. For something like EGFR mutations, which are the oldest target that we test for, we probably still only test close to 80% of people. So one in five still that could benefit from these drugs, isn't getting it.

And everything else is less than that. But one of the most recent publications I've seen from looking at population studies, we're probably getting up above 50% that are being tested, at least for the half dozen or so targets that we have approved drugs for. And the good news is that KRAS is included in all those panels. And so I'm not as worried for KRAS as I am for something like ENTRAK, for example, where you have to do a special RNA fusion panel in order to get that testing. And there may be people out there that are unfortunately passing away without ever being identified.

Dale Shepard, MD, PhD: What do you think has been the biggest barrier to testing and improving the success of people getting tested when they need it?

Nathan Pennell, MD, PhD: I think that in 2022, understanding of the importance of testing is no longer a barrier because oncologists do understand that it's important. Unfortunately, what happens is in all too many cases, patients get their biopsy and then they go somewhere and see an oncologist to talk about treatment. And that biopsy is somewhere not easily reachable to that oncologist. Or when they order the test, the tissue requirements or material requirements are greater than what is available. And so patients don't have enough, essentially, to get all of the testing that is needed. So they may need another biopsy and they may be too ill to do that. And it's much easier just to start chemotherapy and immunotherapy without needing any testing. And so you have to keep in mind that in the future one day you'll re-biopsy it and test. I do think though that we're starting to move into an era of plasma testing.

So we can look for circulating tumor DNA tests are now FDA approved and readily available that'll give you an answer within a week. And for most people, that will end up being good enough, because if you identify any of these mutations or genetic alterations on a plasma test, we know that it's reliable and you can treat based on that. The issue is the sensitivity is still not ideal, and you're probably missing more than a quarter of people with targetable alterations if you just use plasma and not tissue. So you still have to remember that you have to follow up on it with tissue if you don't find something on plasma. But at least coming together, things are better. So one of the things that we have done here for more than a decade at the Cleveland Clinic, which I push every time I talk to someone about this topic, we have something called reflex testing.

So when our pathologists make a diagnosis of lung adenocarcinoma, they reflexively immediately order molecular testing so that shortens the time to getting that information. We've also worked with all of our biopsy colleagues in interventional pulmonary surgery, interventional radiology, to make sure that they really shepherd the tissue appropriately and make sure they get enough material for testing. And so we do a phenomenal job of testing, almost every patient in a very reasonable time. And often when I see the patient for their first consult, we already have that there. And so these are the types of strategies that places can adopt in order to increase and make sure nobody falls through the cracks.

Dale Shepard, MD, PhD: So it looks like G 12 C, great target, good therapies. We have good testing in place. So it looks like everything's moving along well in that direction. What's the next exciting target? What do you think is the next thing that's going to be the big break?

Nathan Pennell, MD, PhD: Well, KRAS mutations are, I think really we're just kind of dipping our toe in this. So the G 12 C is almost half of lung cancer adenocarcinoma, but it's only single digits of pancreas cancer or colorectal cancer or other GI cancers, or ovarian. There's tons of cancers with KRAS mutations that aren't G 12 C. So I think that expanding within that pathway is still a huge area of importance. I think it's sort of, kind of targeted, but trying to capture a larger percentage of people with our immunotherapies, which obviously have revolutionized treatment in many different cancers, and probably most cancers have some role of immunotherapy these days. But we're still only benefiting a relatively small subset of people with this. So expanding on that, I think will be probably absorbing the majority of resources of clinical trials and pharmaceutical companies over the next decade.

Within lung cancer, I do think we may be reaching kind of the diminishing returns phase of finding genomic targets because there's been such good discovery of all of these. And so, yes, we're still getting publications of rare gene fusion targets, but they're becoming, we're now talking about each of them being in less than 1% of people when they come out. And so, I don't know. I don't know if there's another 10 plus percent of patient, single target for which a single drug is going to be working left in lung cancer. I hope I'm wrong. But I don't know. We might have to look past that to something that works in a broader group of people like human immunotherapy.

Dale Shepard, MD, PhD: Sounds good. Well, you've provided some great insights today. Appreciate you being with us.

Nathan Pennell, MD, PhD: Thanks, Dale. I really appreciate being invited to come and talk about this.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting You will receive confirmation once the appointment is scheduled. This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, Subscribe to the podcast on iTunes, Google play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real-time updates from Cleveland Clinic's cancer center experts on our consult QD website at Thank you for listening. Please join us again soon.


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